C-25 carbamate rifamycin derivatives with activity against drug-resistant microbes

ABSTRACT

Compounds of the current invention relate to rifamycin derivatives having antimicrobial activities, including activities against drug-resistant microorganisms. More specifically, compounds of the current invention relate to C-25 carbamate derivatives of rifamycin having another functional group or pharmacophore covalently attached to this position through a carbamate linkage. The resulting compounds exert their antimicrobial activity through a dual-function mechanism and therefore exhibit reduced frequency of resistance.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application,Ser. No. 60/565,497, entitled “C-25 Carbamate Rifamycin Derivatives withActivity against DRUG-Resistant Microbes” filed on Apr. 26, 2004, havingCombrink et al., listed as the inventors, the entire content of which ishereby incorporated by reference.

BACKGROUND OF THE INVENTION

This invention relates to novel rifamycin derivatives havingantimicrobial activity, compositions containing the compounds, andmethods for treatment and prevention of microbial infections. Thecompounds of the current invention are potent antibacterial agentsactive against certain drug-resistant, and particularlyrifamycin-resistant pathogens.

Rifamycins are natural products with potent antimicrobial activity.Examples of the naturally-occurring rifamycins are rifamycin B,rifamycin O, rifamycin R, rifamycin U, rifamycin S, rifamycin SV andrifamycin Y (Brufani et al., 1974). The therapeutic applications of thenaturally-occurring rifamycins are limited due to their poor oralbioavailability, weak activity against Gram-negative pathogens and lowdistribution into the infected tissues. Significant efforts have beenmade toward to identifying semi-synthetic rifamycin derivatives toaddress the deficiencies. As a result, many semi-synthetic rifamycinderivatives with improved spectrums and pharmacological profiles havebeen identified. Among the semi-synthetic compounds, rifampin, rifabutinand rifapetine have been developed into therapeutic agents and arewidely used for the treatment of tuberculosis and other microbialinfections (Farr, Rifamycins).

One of the major problems associated with the rifamycin class ofantimicrobial agents is the rapid development of microbial resistance.Compounds of the current invention are designed to address the rifamycinresistance problem by covalently attaching another functional group tothe C-25 position of rifamycin scaffold that provides an additionalbinding interaction with RNA polymerase or interacts to an additionalenzyme target.

Reference is made to U.S. Pat. No. 4,188,321 that describes a series ofC-25 desacetyl derivatives and Wehrli, Zimmerman et al., 1987, thatdiscloses a series of C-25 rifamycin derivatives modified through anester linkage. The compounds of the current invention are rifamycinderivatives having stable C-25 carbamate functionality, which are novel.

Reference is made to Kump and Bickel, 1973, which describes preparationof a propionate and pivalate esters at C-25. Reference is made to U.S.Pat. No. 5,786,350 that discloses a series of C-36 derivatives ofrifamycins, including derivatives formed by linking the C-3 carboxygroup of a fluoroquinolone to the C-36 position of rifamycins through achemically and metabolically liable ester group. Compounds of thecurrent invention link an antibiotic to the C-25 position of rifamycinsthrough a chemically and metabolically stable carbamate linker.

Reference is also made to International Patent Application PublicationNo. WO 03/045319 A2 which discloses rifamycin derivatives formed bylinking rifamycin and a therapeutic drug and the use of thesederivatives as vehicles for delivering the therapeutic drug. However,the aforementioned reference failed to demonstrate by specific examplesthat any drug is introduced to the C-25 position of a rifamycinmolecule. Derivatives in which the C-25 acetate is replaced by acarbamate linkage are not described and no examples for the preparationof such examples are known.

SUMMARY

One aspect of the current invention is a compound having a Formula I:

or its corresponding quinone form Formula II:

or its salts, hydrates, prodrugs or mixtures thereof. In these Formulas,—NR₂R₃ is a new attachment point for the rifamycin class of antibioticsin which R₂ and R₃ can be a wide variety of substituents including thosecontaining a second antibacterial pharmacophore.

A preferred X in the above structures comprises: —H, —NR₁₁R₁₂,—CH₂—NR₁₁R₁₂, —CH═NNR₁₁R₁₂, —SR₁₃ or -L₃-Q₃, wherein L₃ is a linkerattached to Q₃, and Q₃ represents an antibacterial pharmacophore. R₁₁and R₁₂ independently represent hydrogen, (C₁-C₆)alkyl, or substituted(C₁-C₆)alkyl. Alternatively, R₁₁ and R₁₂, together with the nitrogenatom to which they are attached, can form a 4- to 8-memberedheterocyclic ring, optionally containing one additional heteroatomselected from oxygen, nitrogen and sulfur, wherein one of the carbon ornitrogen atoms is optionally substituted by a (C₁-C₆)alkyl orsubstituted (C₁-C₆)alkyl. R₁₃ represents (C₁-C₆)alkyl or substituted(C₁-C₆)alkyl.

A preferred Y in the above Formula I comprises: —OR₁, wherein R₁represents hydrogen, (C₁-C₆)alkyl, substituted (C₁-C₆)alkyl, —CH₂COOH,or —CH₂CONR₁₁R₁₂. R₁₁ and R₁₂ are defined as above.

A preferred Y in the above Formula II represents ═O.

A preferred Z encompasses ═O, ═NH, or ═NOR₁₄. R₁₄ is —H, alkyl, aryl,heteroaryl or -L₁₁-Q₁₁, wherein L₁₁ is a linker attached to Q₁₁ and Q₁₁represents an antibacterial pharmacophore.

A preferred R₂ and R₃ in the above structures are independently selectedfrom hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, aryl, orheteroaryl. These groups optionally can be further substituted. R₂ andR₃ can also independently represent -L₂₅-Q₂₅. Alternatively, R₂ and R₃,together with the nitrogen to which they are attached, can form a 4- to8-membered heterocyclic ring containing one or two additionalheteroatoms, wherein the carbon or nitrogen atoms of the ring areoptionally substituted with hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, hydroxyl, (C₁-C₆)alkoxy, or -L₂₅-Q₂₅. L₂₅ is alinker attached to Q₂₅ and Q₂₅ represents another antibacterialpharmacophore.

In the above Formulas I and II, X and Y together may form heterocyclicring structures having Formula III, IV, V or VI:

For clarity, structures III-VI are illustrated to show a portion of theoriginal structure of Formulas I and II. In particular, structuresIII-VI show the C-3 and C-4 positions of the rifamycin of Formulas I andII. In these structures, R₁₅ is a group of the formula —NR₂₀R₂₁. R₁₆ ishydrogen, (C₁-C₆)alkyl, OH or NH₂. R₁₇, R₂₀, and R₂₁ independently are(C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, or (C₃-C₈)cycloalkyl.Alternatively, R₂₀ and R₂₁, together with the nitrogen to which they areattached, may form a 4-8 membered heterocyclic ring containing one ortwo additional heteroatoms, wherein the nitrogen atoms are optionallysubstituted with hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl,or (C₃-C₈)cycloalkyl. R₁₈ is (C₁-C₆)alkyl, (C₁-C₆)alkenyl,(C₁-C₆)alkynyl, (C₃-C₈)cycloalkyl, (C₁-C₅)alkylheterocycle, or —NR₂₀R₂₁.R₁₉ is (C₁-C₆)alkyl, (C₁-C₆) alkenyl, (C₁-C₆)alkynyl,(C₃-C₈)cycloalkylene, or —NR₂₀R₂₁.

L₃, L₁₁ and L₂₅ may be the same or different and represent anycombination of 1 to 5 of the following structures: (C₁-C₆)alkylene,(C₁-C₆)alkenylene, (C₁-C₆)alkynylene, (C₃-C₈)cycloalkylene, heterocyclestructure containing 1 to 3 heteroatoms, arylene and heteroarylene,wherein the group is optionally interrupted by 1 to 3 heteroatomsselected from N, O and S, and wherein the carbon or nitrogen atoms ofthe linker group are optionally substituted by 1 to 3 substituentsselected from (C₁-C₆)alkyl, heterocycloalkyl, amino, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, hydroxyl, or (C₁-C₆) alkoxy. All of these groupsoptionally can be further substituted.

Preferred sets of linkers L₃, L₁₁, and L₂₅ may independently be absentor a linker formed by any combination of 0-3 structures shown in FIG. 1.

Q₃, Q₁₁ and Q₂₅ are a pharmacophore, therapeutic drug, or antibacterialagent. Q₃, Q₁₁ and Q₂₅ independently can be a quinolone, anoxazolidinone, a macrolide, an aminoglycoside, a tetracycline or anystructure associated with an antibacterial agent. Preferably, Q₃, Q₁₁and Q₂₅ independently can be a quinolone, a macrolide, or anoxazolidinone core.

A preferred Q₃, Q₁₁ or Q₂₅ pharmacophore comprises Formula VI, FormulaVII, or Formula VIII:

wherein Ri comprises: (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, substituted(C₃-C₆)cycloalkyl, aryl, substituted aryl, heteroaryl, or substitutedheteroaryl; Rii comprises hydrogen, halogen, amino, nitro or methyl; andRiii and Riv independently comprise hydrogen or (C₁-C₆)alkyl.Alternatively, Riii and Riv, together with the carbon atom to which theyare attached, form a 3- to 6-membered carbocyclic ring. A₆ representsC—H, C—F, or N. A₈ represents C—H, C—F, C—Cl, C-Me, C—OMe, C—OCH₂F,C—OCHF₂, or N. A₉ represents CH₂, O or S. The preferred quinolonepharmacophores shown in Formulas VI, VII, and VIII are covalentlycoupled or bonded to the linker L₃, L₁₁ or L₂₅, which in turn iscovalently coupled or bonded to rifamycin through the C₇ carbon of thequinolone core structure. Preferred sets of linkers are any combinationof from one to three structures shown in FIG. 1, where the left side ofthe linker is attached to rifamycin molecule through a C—N, C—O or C—Cbond and the right side of the linker is attached to the quinolonemolecule through a C—N, C—O or C—C bond. A more preferred Q₃, Q₁₁ andQ₂₅ pharmacophore may comprise any of the structures related toquinolones shown in FIG. 2.

Another preferred Q₃, Q₁₁ and Q₂₅ pharmacophore comprises any of thestructural formulas related to the macrolide antibiotics, as shownbelow:

wherein, Ra is hydrogen or hydroxyl. Xa is —O—, —NH—, or —CH₂NH—. Rb is-Xb-Rx, wherein Xb is absent or is any combination of from one to threestructures shown in FIG. 1, where the left side of the linker isattached to the rifamycin molecule through a C—N, C—O or C—C bond, andthe right side of the linker is attached to the macrolide core trough aC—N, C—O or C—C bond. Rx comprises (C₁-C₆)alkyl, substituted(C₁-C₆)alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, or a rifamycin pharmacophore. One of Rc and Rd is a hydrogenatom and the other is selected from hydroxyl, amino-, alkylamino,dialkylamino, or —NH-Xb-Rx. Alternatively, Rc and Rd, together with thecarbon atom to which they are attached, form C═O or C═N—O-Xb-Rx. Re is(C₁-C₆)alkyl, substituted (C₁-C₆)alkyl, or -Xb-Rx. Rf is hydrogen,(C₁-C₆)alkyl, or substituted (C₁-C₆)alkyl. Rg is hydrogen, acetyl orpropionyl group. Rh is methyl or methoxyl group. Ri is —CH₂CHO,—CH₂CH═N—O-Xb-Rx, —CH₂CH₂—NH-Xb-Rx. Rj is hydrogen or methyl. Rk ishydrogen or —CH₂—O-sugar. R₁ is methyl or ethyl. A specific set ofpharmacophores are represented in the structural formulas shown in FIG.3. The preferred therapeutic macrolide pharmacophore, as shown in thethree formulas above, are covalently coupled to the linker or directlyto the rifamycin pharmacophore through C-4″, C-6, C-9, or C-9a of themacrolide. Preferred sets of linkers (“Xb”) are any combination of fromone to three structures shown in FIG. 1, where the left side of thelinker is attached to the rifamycin molecule through a C—N, C—O or C—Cbond and the right side of the linker is attached to the macrolidemolecule through a C—N, C—O or C—C bond.

Another preferred Q₃, Q₁₁ and Q₂₅ pharmacophore comprises any of thestructural formulas related to the oxazolidinone antibiotics, as shownbelow:

wherein Ry and Rz are independently selected from H or F and Xg is L₃,L₁₁ or L₂₅. The preferred oxazolidinone pharmacophore as shown in theformula above is covalently coupled or bonded to the linker L₃, L₁₁ orL₂₅ which in turn is covalently coupled or bonded to the rifamycinmolecule. Preferred sets of linkers are any combination of from one tothree structures shown in FIG. 1, where the left side of the linker isattached to the rifamycin molecule through a C—N, C—O or C—C bond andthe right side of the linker is attached to the oxazolidinone moleculethrough a C—N, C—O or C—C bond.

Another aspect of the current invention comprises a method of treating amicrobial infection in a subject; wherein the subject is any species ofthe animal kingdom. The microbial infection can be caused by a bacteriumor microorganism. The term “subject” refers more specifically to humanand animals, wherein the animals can be used for: pets (e.g. cats, dogs,etc.); work (e.g. horses, cows, etc.); food (chicken, fish, lambs, pigs,etc); and all others known in the art. The method comprisesadministering an effective amount of one or more compounds of thepresent invention to the subject suffering from a microbial infection.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a group of linkers, which are preferred structures for L₃,L₁₁ and L₂₅;

FIG. 2 shows a group of quinolone pharmacophores, which are preferredstructures for Q₃, Q₁₁ and Q₂₅;

FIG. 3 shows a group of macrolide pharmacophores, which are preferredstructures for Q₃, Q₁₁ and Q₂₅;

FIG. 4 shows Scheme 1, wherein a rifamycin derivative with a C-25carbamate linkage is constructed;

FIG. 5 shows Scheme 2, wherein a rifamycin derivative reacts with aquinolone compound;

FIG. 6 shows Scheme 3, wherein a rifamycin derivative reacts with amacrolide compound;

FIG. 7 shows Scheme 4, wherein a rifamycin derivative reacts with anoxazolidinone compound;

FIG. 8 shows Schemes 5a and 5b, wherein a rifamycin derivative with anisooxazole (5a) or dihydroisooxazole (5b) ring is constructed;

FIG. 9 shows Scheme 6, wherein a rifamycin derivative undergoes apalladium catalyzed arylation reaction;

FIG. 10 shows Scheme 7, wherein a rifamycin derivative undergoes apalladium catalyzed arylation reaction; and

FIG. 11 shows Schemes 8a and 8b, wherein a rifamycin undergoes areductive amination reaction.

DETAILED DESCRIPTION

Terms:

The term “alkenyl,” as used herein, refers to a monovalent straight orbranched chain group containing at least one carbon-carbon double bond.The alkenyl groups of this invention can be optionally substituted.

The term “alkenylene,” as used herein, refers to a bivalent straight orbranched chain group containing at least one carbon-carbon double bond.The alkenylene groups of this invention can be optionally substituted.

The term “alkyl,” as used herein, refers to a monovalent, saturated,straight or branched chain hydrocarbon group. Examples of alkyl groupinclude methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,tert-butyl, neo-pentyl, and n-hexyl. The alkyl groups of this inventioncan be optionally substituted.

The term “alkylene,” as used herein, refers to bivalent saturated,straight or branched chain hydrocarbon structures. Examples of alkylenegroups include methylene, ethylene, propylene, iso-propylene,n-butylene, isobutylene, and n-hexylene. The alkylene groups of thisinvention can be optionally substituted.

The term “alkylamino,” as used herein, refers to an amino group (—NH₂),wherein one hydrogen atom is replaced by an alkyl group. Examples ofalkylamino include methylamino, ethylamino, propylamino, andisopropylamino.

The term “alkylthio,” as used herein, refers to an alkyl group, asdefined herein, attached to the parent molecular group through a sulfuratom. Examples of alkylthio include methylthio, ethylthio, propylthio,and isopropylthio.

The term “alkoxy,” as used herein, refers to an alkyl group, aspreviously defined, attached to the parent molecular group through anoxygen atom. Examples of alkoxy include methoxy, ethoxy, propoxy,iso-propoxy, n-butoxy, tert-butoxy, neo-pentoxy and n-hexoxy. The alkoxygroups of this invention can be optionally substituted.

The term “alkynyl,” as used herein, refers to a monovalent straight orbranched chain group of two to six carbon atoms containing at least onecarbon-carbon triple bond. Examples of alkynyl include ethynyl,propynyl, and butynyl. The alkynyl groups of this invention can beoptionally substituted.

The term “alkynylene,” as used herein, refers to a bivalent straight orbranched chain group of two to six carbon atoms containing at least onecarbon-carbon triple bond. Examples of alkynylene include ethynylene,propynylene, and butynylene. The alkynylene groups of this invention canbe optionally substituted

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to protonic activity, i.e., not acting as a protondonor. Examples include hexane, toluene, dichloromethane, ethylenedichloride, chloroform, tetrahydrofuran, N-methylpyrrolidinone, anddiethyl ether.

The term “aryl” as used herein refers to a monovalent carbocyclicaromatic group such as phenyl, naphthyl, and anthracenyl, which can beoptionally substituted.

The term “arylene” as used herein refers to bivalent carbocyclicaromatic groups which can be optionally substituted.

The term “benzyl,” as used herein, refers to —CH₂C₆H₅.

The term “benzyloxy,” as used herein, refers to a benzyl group, asdefined herein, attached to the parent molecular group through an oxygenatom.

The term “carboxaldehyde,” as used herein, refers to —CHO.

The term “cycloalkyl,” as used herein, refers to a monovalent saturatedcarbocyclic group having three to eight carbons such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term “cycloalkylene,” as used herein, refers to bivalent saturatedcarbocyclic groups having three to eight carbons. The cycloalkylenegroups can be optionally substituted.

The term “formyl,” as used herein, refers to —CH(═O).

The term “halogen,” as used herein, refers to fluorine, chlorine,bromine and iodine atoms and the term “halo” refers to —F, —Cl, —Br, and—I as substituent.

The term “heteroaryl,” as used herein, refers to a cyclic aromatic grouphaving five or six ring atoms wherein at least one ring atom is selectedfrom the group consisting of oxygen, sulfur, and nitrogen, and theremaining ring atoms are carbon. Heteroaryl groups of this inventioninclude those derived from furan, imidazole, isothiazole, isoxazole,oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,quinoline, thiazole, 1,3,4-thiadiazole, triazole, and tetrazole.

The term “heteroarylene,” as used herein, refers to a bivalent cyclicaromatic group having five or six ring atoms wherein at least one ringatom is selected from the group consisting of oxygen, sulfur, andnitrogen, and the remaining ring atoms are carbon. The heteroarylenegroup can be optionally substituted.

The term “heteroatom,” as used herein, refers to oxygen, nitrogen orsulfur atom.

The term “heterocycloalkyl” as used herein, refers to a non-aromaticfive-, six- or seven-membered ring or a bi- or tri-cyclic group havingone or more heteroatoms independently selected from oxygen, sulfur, andnitrogen, wherein each 5-membered ring has zero to one double bonds andeach six-membered ring has zero to 2 double bonds. The nitrogen andsulfur heteroatoms can optionally be oxidized, the nitrogen heteroatomcan optionally be quaternized, and any of the above heterocyclic ringscan be fused to an aryl or heteroaryl ring. Representative heterocyclesinclude, but are not limited to: pyrrolidinyl, pyrazolinyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl,oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, morpholinyl,isothiazolidinyl, and tetrahydrofurranyl. The heterocycloalkyl groups ofthis invention can be optionally substituted with one, two, or threesubstituents independently selected from —F, —Cl, —OH, —NO₂, —CN,—C(O)-alkyl, —C(O)-aryl, —C(O)-heteroaryl, —CO₂-alkyl, —CO₂-aryl,—CO₂-heteroaryl, —C(O)NH₂, —C(O)NH-alkyl, —C(O)NH-aryl,—C(O)NH-heteroaryl, —OC(O)-alkyl, —OC(O)-aryl, —OC(O)-heteroaryl,—OC(O)NH₂, —OC(O)NH-alkyl, —OC(O)NH-aryl, —OCONH-heteroaryl,—NHC(O)-alkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHCO₂-alkyl,—NHCO₂-aryl, —NHCO₂-heteroaryl, —NHC(O)NH₂, —NHC(O)NH-alkyl,—NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —SO₂-alkyl, —SO₂-aryl,—SO₂-heteroaryl, —SO₂NH₂, —SO₂NH-alkyl, —SO₂NH-aryl, —SO₂NH-heteroaryl,-alkyl, -cycloalkyl, -cycloheteroalkyl, —CF₃, —CH₂OH, —CH₂NH₂, -aryl,-heteroaryl, -benzyl, -benzyloxy, -aryloxy, -heteroaryloxy, -alkoxy,-methoxymethoxy, -methoxyethoxy, -amino, -benzylamino, -arylamino,-heteroarylamino, -alkylamino, -thio, -arylthio, -heteroarylthio,-benzylthio, -alkylthio, and -methylthiomethyl.

The term “heterocycloalkylene” as used herein, refers to a bivalentnon-aromatic five-, six- or seven-membered ring having one or moreheteroatoms independently selected from oxygen, sulfur and nitrogenwherein each 5-membered ring has zero to one double bonds and eachsix-membered ring has zero to 2 double bonds. The heterocycloalkylenegroups of this invention can be optionally substituted.

The term “hydroxyl,” as used herein, refers to —OH.

The term “protecting group”, as used herein, refers to an easilyremovable group to which are known in the art to protect a functionalgroup, such as hydroxyl and amino, against undesirable reaction duringsynthetic procedures and to be selectively removable. The use ofprotecting groups is well-known in the art for protecting groups againstundesirable reactions during a synthetic procedure and many suchprotecting groups are known (Greene and Wuts, 1991).

The term “pharmaceutically acceptable prodrugs,” as used herein refersto the prodrugs of the compounds of the current invention which aresuitable for use in humans and animals with acceptable toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit to risk ratio, and effective for their intended use.

The term “pharmaceutically acceptable salt,” as used herein refers tothose salts which are suitable for use in humans and animals withacceptable toxicity, irritation, and allergic response, etc., and arecommensurate with a reasonable benefit to risk ratio. Pharmaceuticallyacceptable salts are well known in the art. The salts can be prepared insitu during the final step of isolation and purification of thecompounds of the invention or separately prepared by reacting thecompounds of the invention with an acid or base. Examples ofpharmaceutically acceptable salts are salts of an amino group formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,phosphoric acid, and sulfuric acid or with organic acids such as aceticacid, oxalic acid, maleic acid, tartaric acid, citric acid, succinicacid, or malonic acid. Examples of pharmaceutically acceptable saltsinclude salts of an acid group formed with inorganic bases such assodium hydroxide, sodium carbonate, sodium phosphate, etc. Other metalsalts include lithium, potassium, calcium, and magnesium. Additionalpharmaceutically acceptable salts include ammonium cations formed withcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate, and aryl sulfonate.

The term “pharmaceutically acceptable carrier,” as used herein, refersto a non-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers include carbohydrates such as lactose, glucose and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; glycols; such a propylene glycol; esters such asethyl oleate and ethyl laureate; agar; buffering agents such asmagnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol, and phosphatebuffer solutions, as well as other nontoxic compatible lubricants suchas sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator. Thepharmaceutical compositions of this invention can be administered tohumans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically, bucally,or as an oral, or nasal spray.

The term “pharmacophore” as used herein, represent a structure that isthe key part of a molecule exhibiting certain pharmacological flnction.

The term “prodrug,” as used herein, represents compounds which can betransformed in vivo to the active parent compounds defmed herein.

The term “rifamycin moiety,” as used herein, comprises both its phenolicand quinone forms.

The term “substituted aryl” as used herein refers to an aryl group asdefined herein, substituted by independent replacement of one, two orthree of the hydrogen atoms with —F, —Cl, —OH, —NO₂, —CN, —C(O)-alkyl,—C(O)-aryl, —C(O)-heteroaryl, —CO₂-alkyl, —CO₂-aryl, —CO₂-heteroaryl,—C(O)NH₂, —C(O)NH-alkyl, —C(O)NH-aryl, —C(O)NH-heteroaryl, —OC(O)-alkyl,—OC(O)-aryl, —OC(O)-heteroaryl, —OC(O)NH₂, —OC(O)NH-alkyl,—OC(O)NH-aryl, —OCONH-heteroaryl, —NHC(O)-alkyl, —NHC(O)-aryl,—NHC(O)-heteroaryl, —NHCO₂-alkyl, —NHCO₂-aryl, —NHCO₂-heteroaryl,—NHC(O)NH₂, —NHC(O)NH-alkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl,—SO₂-alkyl, —SO₂-aryl, —SO₂-heteroaryl, —SO₂NH₂, —SO₂NH-alkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, -alkyl, -cycloalkyl, -heterocycloalkyl,—CF₃, —CH₂OH, —CH₂NH₂, -aryl, -heteroaryl, -benzyl, -benzyloxy,-aryloxy, -heteroaryloxy, -alkoxy, -methoxymethoxy, -methoxyethoxy,-amino, -benzylamino, -arylamino, -heteroarylamino, -alkylamino, -thio,-arylthio, -heteroarylthio, -benzylthio, -alkylthio, or-methylthiomethyl.

The term “substituted heteroaryl” as used herein refers to a heteroarylgroup as defined herein substituted by independent replacement of one,two or three of the hydrogen atoms with —F, —Cl, —OH, —NO₂, —CN,—C(O)-alkyl, —C(O)-aryl, —C(O)-heteroaryl, —CO₂-alkyl, —CO₂-aryl,—CO₂-heteroaryl, —C(O)NH₂, —C(O)NH-alkyl, —C(O)NH-aryl,—C(O)NH-heteroaryl, —OC(O)-alkyl, —OC(O)-aryl, —OC(O)-heteroaryl,—OC(O)NH₂, —OC(O)NH-alkyl, —OC(O)NH-aryl, —OCONH-heteroaryl,—NHC(O)-alkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHCO₂-alkyl,—NHCO₂-aryl, —NHCO₂-heteroaryl, —NHC(O)NH₂, —NHC(O)NH-alkyl,—NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —SO₂-alkyl, —SO₂-aryl,—SO₂-heteroaryl, —SO₂NH₂, —SO₂NH-alkyl, —SO₂NH-aryl, —SO₂NH-heteroaryl,-alkyl, -cycloalkyl, -heterocycloalkyl, —CF₃, —CH₂OH, —CH₂NH₂, -aryl,-heteroaryl, -benzyl, -benzyloxy, -aryloxy, -heteroaryloxy, -alkoxy,-methoxymethoxy, -methoxyethoxy, -amino, -benzylamino, -arylamino,-heteroarylamino, -alkylamino, -thio, -arylthio, -heteroarylthio,-benzylthio, -alkylthio, or -methylthiomethyl.

The term “substituted heterocycloalkyl,” as used herein, refers to aheterocycloalkyl group, as defined above, substituted by independentreplacement of one, two or three of the hydrogen atoms with —F, —Cl,—OH, —NO₂, —CN, —C(O)-alkyl, —C(O)-aryl, —C(O)-heteroaryl, —CO₂-alkyl,—CO₂-aryl, —CO₂-heteroaryl, —C(O)NH₂, —C(O)NH-alkyl, —C(O)NH-aryl,—C(O)NH-heteroaryl, —OC(O)-alkyl, —OC(O)-aryl, —OC(O)-heteroaryl,—OC(O)NH₂, —OC(O)NH-alkyl, —OC(O)NH-aryl, —OCONH-heteroaryl,—NHC(O)-alkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHCO₂-alkyl,—NHCO₂-aryl, —NHCO₂-heteroaryl, —NHC(O)NH₂, —NHC(O)NH-alkyl,—NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —SO₂-alkyl, —SO₂-aryl,—SO₂-heteroaryl, —SO₂NH₂, —SO₂NH-alkyl, —SO₂NH-aryl, —SO₂NH-heteroaryl,-alkyl, -cycloalkyl, -heterocycloalkyl, —CF₃, —CH₂OH, —CH₂NH₂, -aryl,-heteroaryl, -benzyl, -benzyloxy, -aryloxy, -heteroaryloxy, -alkoxy,-methoxymethoxy, -methoxyethoxy, -amino, -benzylamino, -arylamino,-heteroarylamino, -alkylamino, -thio, -arylthio, -heteroarylthio,-benzylthio, -alkylthio, or -methylthiomethyl.

The term “substituent,” as used herein, refers to —F, —Cl, —OH, —NO₂,—CN, —C(O)-alkyl, —C(O)-aryl, —C(O)-heteroaryl, —CO₂-alkyl, —CO₂-aryl,—CO₂-heteroaryl, —C(O)NH₂, —C(O)NH-alkyl, —C(O)NH-aryl,—C(O)NH-heteroaryl, —OC(O)-alkyl, —OC(O)-aryl, —OC(O)-heteroaryl,—OC(O)NH₂, —OC(O)NH-alkyl, —OC(O)NH-aryl, —OCONH-heteroaryl,—NHC(O)-alkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHCO₂-alkyl,—NHCO₂-aryl, —NHCO₂-heteroaryl, —NHC(O)NH₂, —NHC(O)NH-alkyl,—NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —SO₂-alkyl, —SO₂-aryl,—SO₂-heteroaryl, —SO₂NH₂, —SO₂NH-alkyl, —SO₂NH-aryl, —SO₂NH-heteroaryl,-alkyl, -cycloalkyl, -heterocycloalkyl, —CF₃, —CH₂OH, —CH₂NH₂, -aryl,-heteroaryl, -benzyl, -benzyloxy, -aryloxy, -heteroaryloxy, -alkoxy,-methoxymethoxy, -methoxyethoxy, -amino, -benzylamino, -arylamino,-heteroarylamino, -alkylamino, -thio, -arylthio, -heteroarylthio,-benzylthio, -alkylthio, or -methylthiomethyl.

Abbreviations:

Abbreviations as used herein have the meanings known by one skilled inthe art. Specifically, Ac represents acetyl group, AOC representsallyloxycarbonyl group, BOC represents t-butoxycarbonyl group, Bnrepresents benzyl group, Bu represents butyl group, Bz representsbenzoyl group, Cbz represents benzyloxycarbonyl group, CDI representscarbonyldiimidazole, DCM represents dichloromethane, DMAP represents4-N,N-dimethylaminopyridine, DME represents 1,2-dimethoxyethane, DMFrepresents N,N-dimethylformamide, DMSO represents dimethyl sulfoxide, Etrepresents ethyl group, EtOAc represents ethyl acetate, Me representsmethyl group, MEM represents 2-methoxyethoxymethyl group, MOM representsmethoxylmethyl group, NMP represents N-methylpyrrolidinone, Phrepresents phenyl group, Pr represents propyl group, TEA representstriethylamine, TFA represents trifluoroacetic acid, THF representstetrahydrofuran, TMS, trirnethylsilyl group, and Ts representsp-toluenesulfonyl group.

Broadly, one aspect of the present invention comprises a compound havinga Formula I:

or its corresponding quinone form having a Formula II:

or its salts, hydrates, prodrugs or mixtures thereof;wherein,

-   X is hydrogen, —NR₁₁R₁₂, —CH₂NR₁₁R₁₂, —C═NNR₁₁R₁₂, —SR₁₃, or -L₃-Q₃,    -   wherein L₃ is any combination of 1 to 5 of the following        structures: (C₁-C₆)alkylene, (C₁-C₆)alkenylene,        (C₁-C₆)alkynylene, (C₃-C₈)cycloalkylene, heterocycle having 1 to        3 heteroatoms, arylene, and heteroarylene, wherein L₃ optionally        has any combination of 1 to 3 heteroatoms selected from N, O,        and S, and wherein the carbon or nitrogen atoms of L₃ are        optionally substituted by any combination of 1 to 3 substituents        selected from (C₁-C₆)alkyl, heterocycloalkyl, amino,        (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, hydroxyl, and        (C₁-C₆)alkoxy,    -   wherein R₁₁ and R₁₂ independently are hydrogen, (C₁-C₆)alkyl, or        substituted (C₁-C₆)alkyl, or        -   R₁₁ and R₁₂, together with the nitrogen atom to which they            are attached, form a 4- to 8-membered heterocyclic ring,            optionally containing a second heteroatom selected from            oxygen, nitrogen and sulfur, wherein one of the carbon or            nitrogen atoms of the heterocyclic ring is optionally            substituted by (C₁-C₆)alkyl or substituted (C₁-C₆)alkyl, and    -   wherein R₁₃ is (C₁-C₆)alkyl or substituted (C₁-C₆)alkyl;-   Y is OR₁, when the compound is the Formula I,    -   wherein R₁ is hydrogen, (C₁-C₆)alkyl, substituted (C₁-C₆)alkyl,        —CH₂COOH, or —CH₂CONR₁₁R₁₂, or    -   Y is ═O, when the compound is the Formula II; or-   X and Y, together with C-3 and C-4 of the Formula I or Formula II,    join together to form a heterocyclic ring as depicted in any of    Formulas III, IV, V and VI:    -   wherein R₁₅ is —NR₂₀R₂₁,        -   R₁₆ is hydrogen, (C₁-C₆)alkyl, OH or NH₂,        -   R₁₇ is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkenyl,            (C₁-C₆)alkynyl, (C₃-C₈)cycloalkyl, aryl, heteroaryl, or            heterocycloalkyl,        -   R₁₈ is (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl,            (C₃-C₈)cycloalkyl, aryl, heteroaryl, —NR₂₀R₂₀, or            heterocycloalkyl,        -   R₁₉ is (C₁-C₆)alkyl or —NR₂₀R₂₁,        -   R₂₀ and R₂₁, independently are alkyl, cycloalkyl, aryl, or            heteroaryl, or        -   R₂₀ and R₂₁, together with the nitrogen atom to which they            are attached, form a 4-8 membered heterocyclic ring            containing one or two heteroatoms optionally substituted            with hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl,            (C₃-C₈)cycloalkyl;-   Z is ═O, ═NH or ═NOR₁₄,    -   wherein R₁₄ is —H, alkyl, aryl, heteroaryl or -L₁₁-Q₁₁,        -   wherein L₁₁ is any combination of 1 to 5 of the following            structures: (C₁-C₆)alkylene, (C₁-C₆)alkenylene,            (C₁-C₆)alkynylene, (C₃-C₈)cycloalkylene, heterocycle            containing 1 to 3 heteroatoms, arylene, and heteroarylene,            wherein L₁₁ optionally has any combination of 1 to 3            heteroatoms selected from N, O and S, and wherein the carbon            or nitrogen atoms of L₁₁ are optionally substituted by any            combination of 1 to 3 substituents selected from            (C₁-C₆)alkyl, heterocycloalkyl, amino, (C₁-C₆)alkylamino,            di(C₁-C₆)alkylamino, hydroxyl, and (C₁-C₆)alkoxy;-   R₂ and R₃ independently are hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkenyl,    (C₁-C₆)alkynyl, aryl, heteroaryl or -L₂₅-Q₂₅,    -   wherein L₂₅ is any combination of 1 to 5 of the following        structures: (C₁-C₆)alkylene, (C₁-C₆)alkenylene,        (C₁-C₆)alkynylene, (C₃-C₈)cycloalkylene, heterocycle containing        1 to 3 heteroatoms, arylene, and heteroarylene, wherein L₂₅        optionally has any combination of 1 to 3 heteroatoms selected        from N, O and S, and wherein the carbon or nitrogen atoms of L₂₅        are optionally substituted by any combination of 1 to 3        substituents selected from (C₁-C₆)alkyl, heterocycloalkyl,        amino, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, hydroxyl, and        (C₁-C₆)alkoxy, or-   R₂ and R₃, together with the nitrogen atom to which they are    attached, form a 4- to 8-membered heterocyclic ring containing one    or two heteroatoms, wherein the carbon or nitrogen atoms of the ring    are optionally substituted with one or more of hydrogen,    (C₁-C₆)alkyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, hydroxyl, and    (C₁-C₆)alkoxy; and-   Q₃, Q₁₁ and Q₂₅ are a pharmacophore, therapeutic drug, or    antibacterial agent comprising a quinolone, a macrolide, an    oxazolidinone, an aminoglycoside, a tetracycline or any    antibacterial pharmacophore.    Compositions:

The compounds of the current invention are rifamycin derivatives ofFormula I and Formula II, which have been labeled at the C₃, C₄, C₁₁,C₂₅ and C₃₆ positions for illustration purposes. Formula I and FormulaII are different in their oxidation states and can be transformed fromone to the other by utilizing an oxidation or reduction reaction. In oneaspect, compounds of the current invention contain many asymmetric andgeometric centers. In some cases, one or more of the asymmetric orgeometric centers can be converted to their opposite configurations.These stereoisomers of rifamycin are within the scope of the presentinvention.

EXAMPLE 1

These examples are intended for illustration purposes only and are notintended to limit the scope of this invention.

A compound having a structure of Formula I:

or its quinone form Formula II:

In these structures, X represents a hydrogen, a substituent or -L₃-Q₃. Xcan be the substituent —NR₁₁R₁₂, —CH₂NR₁₁R₁₂, —C═NNR₁₁R₁₂, or —SR₁₃. R₁₁and R₁₂ independently can be hydrogen, (C₁-C₆)alkyl, or substituted(C₁-C₆)alkyl. Alternatively, R₁₁ and R₁₂, together with the nitrogenatom to which they are attached, can form a 4- to 8-memberedheterocyclic ring, optionally containing an additional heteroatomselected from oxygen, nitrogen and sulfur, wherein one of the carbon ornitrogen atoms of the heterocyclic ring is optionally substituted by(C₁-C₆)alkyl or substituted (C₁-C₆)alkyl. R₁₃ can be (C₁-C₆)alkyl orsubstituted (C₁-C₆)alkyl.

Y in Formula I represents the formula —OR₁. The C-4 position ofrifamycins can tolerate a substituent group, and these compounds mayhave activity against microorganisms. R₁ can be hydrogen or asubstituted or unsubstituted lower alkyl group of between 1 and 6 carbonatoms. In addition, R₁ can be a —CH₂COOH, or a —CH₂C(O)NR₁₁R₁₂ group.Compounds with these substituents can be conveniently derived fromrifamycin B, although they can be prepared from other rifamycincompounds as well. The structure of the amide group —C(O)NR₁₁R₁₂ hereincan be varied from a simple amide, wherein R₁₁ and R₁₂ are both hydrogenatoms, to a more complex structure, wherein either one or both R₁₁ andR₁₂ independently are lower alkyl groups between 1 to 6 carbon atoms.The alkyl groups can be substituted by a variety of substituent groups.Examples of the substituent groups include alkyl, substituted alkyl,amino, alkylamino, dialkylamino, hydroxyl, alkoxy, or halogens.Furthermore, R₁₁ and R₁₂ can join together with the nitrogen atom towhich they are attached to form a 4- to 8-membered heterocyclic ring.This ring can optionally contain one additional heteroatom selected fromoxygen, nitrogen and sulfur, wherein one of the carbon or nitrogen atomsis optionally substituted by a lower alkyl or substituted lower alkylgroup. A preferred Y in Formula II is ═O.

In the above Formulas I and II, X and Y together may form heterocyclicring structures having Formula III, IV, V or VI:

For clarity, structures III-VI are illustrated to show a portion of theoriginal structure of Formulas I and II. In particular, structuresIII-VI show the C-3 and C-4 positions of the rifamycin of Formulas I andII. In these structures, R₁₅ is a group of the formula —NR₂₀R₂₁. R₁₆ ishydrogen, (C₁-C₆)alkyl, OH or NH₂. R₁₇, R₂₀, and R₂₁ independently are(C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, or (C₃-C₈)cycloalkyl.Alternatively, R₂₀ and R₂₁, together with the nitrogen to which they areattached, may form a 4-8 membered heterocyclic ring containing one ortwo additional heteroatoms, wherein the nitrogen atoms are optionallysubstituted with hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl,or (C₃-C₈)cycloalkyl. R₁₈ is (C₁-C₆)alkyl, (C₁-C₆)alkenyl,(C₁-C₆)alkynyl, (C₃-C₈)cycloalkyl, (C₁-C₅)alkylheterocycle, or —NR₂₀R₂₁.R₁₉ is (C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, (C₃-C₈)cycloalkyl,or —NR₂₀R₂₁.

Z in the above Formulas I and II can be ═O, ═NH or ═NOR₁₄. R₁₄ can be—H, alkyl, aryl, heteroaryl or -L₁₁-Q₁₁.

R₂ and R₃ in the above structures are independently selected from agroup consisting of hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkenyl,(C₁-C₆)alkynyl, aryl, heteroaryl, all of which may be optionallysubstituted, and -L₂₅-Q₂₅. Alternatively, R₂ and R₃ can join togetherwith the nitrogen to which they are attached to form a 4- to 8-memberedheterocyclic ring containing one or two heteroatoms, wherein the carbonor nitrogen atoms of the ring are optionally substituted with hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, hydroxyl,(C₁-C₆)alkoxy or -L₂₅-Q₂₅. Q₂₅ is another antibacterial agent.

The linker groups L₃, L₁₁, and L₂₅ can be groups with various length,rigidity and properties. The linker groups may be any combination of 1to 5 of the following structures: (C₁-C₆)alkylene, (C₁-C₆)alkenylene,(C₁-C₆)alkynylene, (C₃-C₈)cycloalkylene, heterocycle having 1 to 3heteroatoms, arylene, and heteroarylene. The linker groups optionallycan have any combination of 1 to 3 heteroatoms selected from N, O and S.The carbon or nitrogen atoms of the linker groups optionally can besubstituted by any combination of 1 to 3 substituents selected from(C₁-C₆)alkyl, heterocycloalkyl, amino, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, hydroxyl, and (C₁-C₆)alkoxy. Examples of the linkergroups are any combination of from one to three structures shown in FIG.1.

As illustrated by Formula I and Formula II, the left-hand side of thelinker group L₃, L₁₁, or L₂₅ is covalently bonded or attached to therifamycin pharmacophore and the right-hand side of the linker iscovalently bonded or attached to an antibiotic pharmacophore representedby Q₃, Q₁₁ or Q₂₅. Pharmacophore Q₃, Q₁₁, or Q₂₅ can be any structureassociated with an antibacterial agent. Examples of pharmacophoresinclude structures associating to the macrolide class, thefluoroquinolone class, the non-fluoroquinolone class, the oxazolidinoneclass, the tetracycline class, the aminoglycoside class, the beta-lactamclass, the sulfonamide class, the trimethoprim class, the glycopeptideclass, the lipopeptide class, and others.

In a preferred embodiment, the pharmacophore Q₃, Q₁₁ or Q₂₅ is astructure related to the fluoroquinolone or non-fluoroquinolone class ofantimicrobial agents selected from Formula VII, VIII and VIX:

The substituents or groups in Formulas VII, VIII and VIX are as follows:Ri represents (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, substituted(C₃-C₆)cycloalkyl, aryl, substituted aryl, heteroaryl, or substitutedheteroaryl; Rii represents a hydrogen, halogen, amino, nitro or methylgroup; Riii and Riv independently represent hydrogen or (C₁-C₆)alkyl, orRiii and Riv, together with the carbon atom to which they are attached,form a 3- to 6-membered ring; A₆ represents C—H, C—F, or N; A₈represents C—H, C—F, C—Cl, C-Me, C—OMe, C—OCH₂F, C—OCHF₂, or N; and A₉represents CH₂, O or S.

In another more preferred embodiment, Q₃, Q₁₁, and Q₂₅ independently areany quinolone structure illustrated in FIG. 2, and linkers L₃, L₁₁ andL₂₅ independently are any combination of from one to three structuresshown in FIG. 1, wherein the left-hand side of the linker group isattached to the rifamycin pharmacophore and the right-hand side of thelinker group is attached to the quinolone structure.

In another preferred embodiment, Q₃, Q₁₁, and Q₂₅ independently are anystructure related to the macrolide class of antibiotics, which can be a14-membered ring, a 15-membered ring or a 16-membered ring macrolide, asshown below:

wherein the substituents in the above figure are as follows: Ra ishydrogen or hydroxyl; Xa is —O—, —NH—, or —CH₂NH—; Rb is -Xb-Rx, whereinXb is absent or is the linker group L₃, preferably having anycombination of from one to three of the structures shown in FIG. 1; Rxis (C₁-C₆)alkyl, substituted (C₁-C₆)alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, or a rifamycin pharmacophore; one ofRc or Rd is a hydrogen atom while the other constituent is hydroxyl,amino, alkylamino, dialkylamino, or —NH-Xb-Rx; or both Rc and Rd,together with the carbon atom to which they are attached, form C═O orC═N—O—X-Rx, wherein Xb and Rx are defined above; Re is (C₁-C₆)alkyl,substituted (C₁-C₆)alkyl, or -Xb-Rx, wherein Xb and Rx are as definedabove; Rf is hydrogen, (C₁-C₆)alkyl, or substituted (C₁-C₆)alkyl; Rg isa hydrogen, acetyl or propionyl group; Rh is a methyl or methoxyl group;Ri is —CH₂CHO, —CH₂CH═N—O-Xb-Rx, or —CH₂CH₂—NH-Xb-Rx, wherein Xb and Rxare as defined above; Rj is hydrogen or methyl; Rk is hydrogen or—CH₂—O-sugar; and R1 is methyl or ethyl.

Examples of macrolide antibiotics include erythromycin,erythromycylamine, clarithromycin, azithromycin, roxithromycin,dirithromycin, flurithromycin, oleandomycin, telithromycin, cethromycin,leucomycin, spiramycin, tylosin, rokitamycin, miokamycin, josamycin,rosaramycin, virginiamycin, and midecamycin. The preferred linkingpoints on a macrolide structure are the C-4″, C-6, C-9 or C9a positionas illustrated above.

In a more preferred embodiment, pharmacophores Q₃, Q₁₁ and Q₂₅independently are a macrolide group selected from any of those shown inFIG. 3 and linkers L₃, L₁₁ and L₂₅ independently are any combination offrom one to three structures shown in FIG. 1, wherein the left-hand sideof the linker group is attached to the rifamycin structure and theright-hand side of the linker group is attached to the macrolidestructure.

In another preferred embodiment, the pharmacophores Q₃, Q₁₁ and Q₂₅independently comprise a structure related to the oxazolidinoneantibiotics, as shown below:

wherein Ry and Rz are independently selected from H or F, and Xg is L₃,L₁₁ or L₂₅. The preferred oxazolidinone pharmacophore as shown in theformula above is covalently coupled or bonded to the appropriate linkerL₃, L₁₁, or L₂₅ which in turn is covalently coupled or bonded to therifamycin molecule. Preferred sets of linkers L₃, L₁₁, and L₂₅ are anycombination of from one to three structures shown in FIG. 1, in whichthe left side of the linker is attached to the rifamycin moleculethrough a C—N, C—O or C—C bond, and the right side of the linker isattached to the oxazolidinone molecule through a C—N, C—O or C—C bond.Preferred antibiotic compounds of the invention are as follows:25-O-desacetyl-(1-carbonyl-4-methyl-piperazine) 3-morpholino rifamycinS, 25-O-desacetyl-(1-carbonyl-isobutylamino) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-allylamino) 3-morpholino rifamycin S,25-O-desacetyl(1-carbonyl-2-(4-methyl-piperazin-1-yl)-ethylamine)3-morpholino rifamycin S, 25-O-desacetyl(1-carbonyl-2-diethylamine)3-morpholino rifamycin S,25-O-desacetyl-(1-carbonyl-3-imidazol-1-yl-propylamine) 3-morpholinorifamycin S, 25-O-desacetyl(1-carbonyl-1-(4-fluorophenyl)-piperazine)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-1-(3-trifluoromethylbenzylamino)) 3-morpholinorifamycin S, 25-O-desacetyl-(carbonyl-1-pyrrolidino) 3-morpholinorifamycin S, 25-O-desacetyl (carbonyl-benzyl) 3-morpholino rifamycin S,25-O-desacetyl-(4-carbonyl-1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(8-chloro-1-cyclopropyl-7-[4-(1-carbonyl)-piperazin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(1-carbonyl-(2-pyridin-2-yl-ethylamine)) 3-morpholinorifamycin S, 25-O-desacetyl-(1-carbonyl-2-thiophen-2-yl-ethylamine)3-morpholino rifamycin S, 25-O-desacetyl-(1-carbonyl-2-aminoethanol)3-morpholino rifamycin S, 25-O-desacetyl-(carbonyl-methylamino)3-morpholino rifamycin S, 25-O-desacetyl-(carbonyl-4-chlorobenzyl)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-naphthalen-1-ylmethyl-amino) 3-morpholinorifamycin S, 25-O-desacetyl-(carbonyl-3-phenylpropylamino) 3-morpholinorifamycin S, 25-O-desacetyl-(carbonyl-3-phenylethylamino) 3-morpholinorifamycin S, 25-O-desacetyl-(carbonyl-4-methoxybenzylamino) 3-morpholinorifamycin S, 25-O-desacetyl-((2-amino-ethyl)-carbamic acid6-[6-(4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-oxacyclotetradec-4-yloxy]-4-methoxy-2,4-dimethyl-tetrahydro-pyran-3-ylester) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-2-ethyl-octahydro-pyrrolo[3,4-c]pyrrole)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N,N-dimethylethylenediamine) 3-morpholinorifamycin S,25-O-desacetyl-(carbonyl-2-(1-methyl-pyrrolidin-2-yl)-ethylamine)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-2-pyrrolidin-1-yl-ethylamine) 3-morpholinorifamycin S, 25-O-desacetyl-(carbonyl-1-benzyl-piperidin-4-ylamine)3-morpholino rifamycin S, 25-O-desacetyl-(carbonyl-4-phenyl-butylamine)3-morpholino rifamycin S, 25-O-desacetyl-(carbonyl-[1,4′]bipiperidinyl)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-(4-aminomethyl-phenyl)-dimethyl-amine)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N′-benzyl-N,N-dimethyl-ethane-1,2-diamino)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-2-(4-chloro-phenyl)-ethylamine) 3-morpholinorifamycin S, 25-O-desacetyl-(carbonyl-3-chloro-benzylamine) 3-morpholinorifamycin S, 25-O-desacetyl-(carbonyl-4-nitro-benzylamine) 3-morpholinorifamycin S, 25-O-desacetyl-(carbonyl-N-(quinolin-3-yl-methylamino))3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-prop-2-ynylamino) 3-morpholino rifamycin S,25-O-deacetyl cyclic-21,23-(1-methylethylideneacetal)-(carbonyl-prop-2-ynylamino)-3-morpholino-rifamycin S,25-O-desacetyl-(carbonyl-[3-(3-amino-prop-1-ynyl)-phenyl]-methanol)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-3-quinolin-3-yl-prop-2-ynylamine) 3-morpholinorifamycin S,25-O-desacetyl-(carbonyl-C-[3-(2-methoxy-phenyl)-isoxazol-5-yl]-methylamino)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-C-(3-pyridin-2-yl-isoxazol-5-yl)-methylamino)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-(3-acetyl-isoxazol-5-ylmethylamino)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-hydroxy-N′-phenyl-4-(2-piperazin-1-yl-ethylamino)-3-trifluoromethyl-benzamidine)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(2-methyl-1H-indol-5-yl)-4-piperazin-1-yl-3-trifluoromethyl-benzamide)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(5-methoxy-pyridin-3-yl)-4-piperazin-1-yl-3-trifluoromethyl-benzamide)3-morpholino rifamycin S, 25-O-desacetyl-(carbonyl-N-(4-piperidone)cyclic-21, 23-(1-methylethylidene acetal) 3-morpholino rifamycin S25-O-desacetyl-(carbonyl-N-(1-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(7-(3-amino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(7-(4-amino-piperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(7-(3-amino-piperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(3-pyrrolidone)cyclic-21,23-(1-methylethylidene acetal)-(3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-(4-pyrrolidin-3-yl-piperazin-1-yl)-1,4-dihydro-quinoline-3-carboxylicacid 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(7-[3-(2-amino-acetylamino)-pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(7-[4-(2-amino-acetyl)-piperazin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(7-[4-(Azetidine-3-carbonyl)-3-methyl-piperazin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(7-[4-(azetidine-3-carbonyl)-piperazin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(7-(3-amino-pyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(8-chloro-1-cyclopropyl-6-fluoro-7-(3-formylamino-pyrrolidin-1-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid)-3-morpholino-11-deoxy-11-hydroxyiminorifamycin S,25-O-desacetyl-(carbonyl-N-(2-dimethylamino-ethyl)-3-morpholino-11-deoxy-11-hydroxyiminorifamycinS.

EXAMPLE 2

Administration to a Subject:

The pharmaceutical composition of the present invention comprises atherapeutically effective amount of a compound of the current inventionformulated together with one or more pharmaceutically acceptablecarriers. Injectable preparations can be formulated according to theknown art using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation can also be a sterileinjectable solution, suspension or emulsion in a nontoxic parenterallyacceptable diluent or solvent, for example, as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that can beemployed are water, Ringer's solution, U.S.P. and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. The injectable formulationscan be sterilized, for example, by filtration through abacterial-retaining filter, or by incorporating sterilizing agents inthe form of sterile solid compositions which can be dissolved ordispersed in sterile water or other sterile injectable medium prior touse. In order to prolong the effect of a drug, it is often desirable toslow the absorption of the drug through subcutaneous or intramuscularinjection. This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, can depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formscan contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils, glycerol, tetrahydrofurfuryl alcohol,polyethylene glycols and fatty acid esters of sorbitan, and mixturesthereof. Besides inert diluents, the oral compositions can also includeadjuvants such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, and perfuming agents.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphate andthe following: 1) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and silicic acid, 2) binders such as,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, 3) humectants such as glycerol, 4) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, 5) solutionretarding agents such as paraffin, 6) absorption accelerators such asquaternary ammonium compounds, 7) wetting agents such as, cetyl alcoholand glycerol monostearate, 8) absorbents such as kaolin and bentoniteclay, and 9) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof. In the case of capsules, tablets and pills, the dosageform can also comprise buffering agents. Solid compositions of a similartype can also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like. The solid dosageforms of tablets, dragees, capsules, pills, and granules can be preparedwith coatings and shells such as enteric coatings and other coatingswell known in the pharmaceutical formulating art. They can optionallycontain opacifying agents and can also be of a composition that theyrelease the active ingredient only, or preferentially, in a certain partof the intestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active compounds can also be in microencapsulated formwith one or more excipients as noted above.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as can be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention. Theointments, pastes, creams and gels can contain, in addition to an activecompound of this invention, excipients such as animal and vegetablefats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays can additionally contain customary propellants such aschlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

According to the methods of treatment of the present invention,bacterial infections are treated or prevented in a patient such as ahuman or animal by administering to the patient a therapeuticallyeffective amount of a compound of the invention, in such amounts and forsuch time as is necessary to achieve the desired therapeutic effects.The term “therapeutically effective amount” of a compound of theinvention is meant a sufficient amount of the compound to treatbacterial infections, at a reasonable benefit to risk ratio applicableto any medical treatment. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific therapeutically effective dose level forany particular patient will depend upon a variety of factors includingthe disorder being treated and the severity of the disorder; theactivity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed; and like factors well known in the medical arts.

The total daily dose of the compounds of this invention administered toa human or animals in single or in divided doses can be in amounts, forexample, from about 0.1 to about 100 mg/kg body weight or preferablyfrom about 0.25 to about 25 mg/kg body weight. Single dose compositionscan contain such amounts or submultiples thereof to make up the dailydose. In general, treatment regimens according to the present inventioncomprise administration to an infected patient of such treatment fromabout 10 mg to about 2000 mg of the compounds of this invention per dayin single or multiple doses. The compounds of current invention can beadministrated orally, rectally, parenterally, intracisternally,intravaginally, intraperitoneally, topically, bucally, or as an oral ornasal spray.

Biological Activity:

Representative compounds were assayed for antimicrobial activity asfollows: Minimum Inhibitory Concentrations (“MICs”) were determined bythe microbroth dilution method as per NCCLS guidelines (NationalCommittee for Clinical Laboratory Standards, 2000), except that allgrowth incubations were conducted at 37° C. Bacterial cultures weretested in the following bacteriological media: S. aureus, S.epidermidis, and E. coli in Cation-Adjusted Mueller-Hinton Broth, S.pneumoniae in THY Broth supplemented with 1 mg/mL catalase under 5% CO₂atmosphere, S. pyogenes in THY Broth, E. faecalis in BHI Broth, H.influenzae in BHI Broth supplemented with 0.75 μL of 1 mg/mL NAD and 150μL of 1 mg/ml hematin per 5 mL, and M smegmatis in Middlebrook Brothplus ADC Enrichment. The antimicrobial activity of the example compoundsof the current invention are shown in Table 1. TABLE 1 Antimicrobialactivity (MIC, mcg/ml) of selected compounds cipro- Organism rifampinfloxacin Example 4-69 Staphylococcus aureus rifS 0.008 0.25  0.002-1.95 ATCC29213 Staphylococcus aureus rifR 7.8 0.25  2.0->64 ATCC29213rpoB^(H418Y) Staphylococcus aureus rifR >64 0.25  0.98->64 ATCC29213rpoB^(D417Y) Staphylococcus epidermidis rifS 0.03 0.125 0.0001-0.8  ATCC12228 Streptococcus pneumoniae rifS 0.061 1 0.00006-25.5   ATCC6303Streptococcus pyogenes rifS 0.013 0.5  0.002-2    ATCC19615 Enterococcusfaecalis rifS 0.98 0.5  0.25-62   ATCC29212 Haemophilus influenzae rifS0.24 0.008  0.06->51 ATCC10211 Escherichia coli rifS 16 0.03  3.9->64ATCC25922 Mycobacterium smegmatis rifS 64 0.125 0.063-31   ATCC700084^(a) For strain MT1222 see: Ince & Hooper, Antimicrobial Agents andChemotherapy, 2000, vol. 44, pp. 3344-50.

S. aureus ATCC 2213, S. epidermidis ATCC 12228, S. pneumoniae ATCC6303,S. pyogenes ATCC 19615 and E. faecalis ATCC 29212 arerifampin-susceptible Gram-positive strains. Rifampin exhibits excellentactivity against these organisms with MICs between 0.03 and 1.3 μg/ml.The compounds of the current invention show further improved activityagainst these strains with MICs as low as 0.0001 μmg/ml. H. influenzaeATCC 10211 and E. coli ATCC 25922 are Gram-negative bacteria. Rifampinhas intrinsic weaker activity against these organisms with MICs between0.24 and 16 μg/ml. Compounds of the current invention also demonstrateimproved activity against these strains with MICs as low as 0.06 μg/ml.In addition, rifampin exhibits low activity against a mycobacterialstrain M smegamatis ATCC 700084 with a MIC 64 μg/ml. Certain compoundsof the current invention show potent activity against this strain with aMIC 0.06 μg/ml.

Most importantly, compounds of the current invention demonstrateexcellent activity against rifampin-resistant organisms. S. aureus ATCC29213 RpoB^(H418Y) is a rifampin-resistant strain with a mutation in RNApolymerase. This mutation results in a significant increase in the MICfor rifampin to 8 μg/ml. Compounds of the current invention exhibitpotent activity against this strain with a MIC as low as 2 μg/ml. S.aureus ATCC 29213 RpoB^(D417Y) is a high level rifampin-resistant straindue to a RNA polymerase mutation with a MIC >64 μg/ml for rifampin.Compounds of the current invention are potent against this highlyrifampin-resistant strain with MICs in the 0.98 μg/ml level.

EXAMPLE 3

Synthetic Methods

The compounds of the current invention can be better understood inconnection with the following synthetic schemes. The syntheticprocedures shown in Schemes 1 to 8 are for illustration purposes and arenot intended to limit the scope of the invention. It will be apparent toone skilled in the art that the compounds of the current invention canbe prepared by a variety of synthetic routes, including but not limitedto substitution of appropriate reagents, solvents or catalysts, changeof reaction sequence, and variation of protecting groups. The groups Ra,Rc, Rd, Re, Rf, Rp, R₂₉, R₃₀, R₃₁, R₃₂, R₃₃, Ry, Rz, Rx, L₃, L₁₁, L₂₅,Q₃, Q₁₁, Q₂₅, Xa, Xg and X₂ in schemes 1 to 8 are defined below orelsewhere.

Scheme 1, shown in FIG. 4, illustrates that compounds of Formula XIIIare prepared by reacting a 25-O-desacetyl rifamycin S acetonide ofFormula X, with carbonyl diimidazole to give the imidazole carboxylate,XI. The imidazole is activated by treating the compound with analkylating agent such as benzyl bromide, or trimethyloxoniumtetrafluoroborate, to give XII. The activated carbamate is treated withan amine to give the desired carbamate, XIII. The acetonide can beremoved with mild aqueous acid hydrolysis or the product can be furtherfunctionalized as shown in Schemes 2 to 8.

One specific example of the current invention is illustrated by Scheme2, shown in FIG. 5, where rifamycin25-O-carbonyl-1-benzy-3H-imidazol-1-ium bromide (XII, X is morpholino)reacts with quinolone compounds of formula 101 to give products ofFormula XIV. It will be apparent to one skilled in the art thatrifamycin 25-O-carbonyl-1-benzy-3H-imidazol-1-ium bromide (XII, X ismorpholino) can be replaced by other rifamycin analogs of Formula XIIand the quinolone compound 101 can be replaced by other pharmacophorewithin the gyrase/topoisomerase IV inhibitor family. The reaction isperformed in an aprotic solvent catalyzed by an organic or inorganicbase. Examples of solvents suitable for this reaction are DCM, DCE, THF,DMSO, DMF, and NMP. Examples of bases are NMM, TEA, DBU, etc. Undercertain circumstances, excess of 101 can be used as base.

Another specific example is illustrated by Scheme 3, shown in FIG. 6,where rifamycin 25-O-carbonyl-1-benzy-3H-imidazol-1-ium bromide (XII,X₃=morpholino) reacts with a macrolide compound of formula 102, whereinRp is a hydrogen or a hydroxyl protecting group such as acetyl orbenzoyl, to give product of Formula XV. It will be apparent to oneskilled in the art that 25-O-(carbonyl-1-benzy-3H-imidazol-1-iumbromide) rifamycin S (XII, X₃=morpholino) can be replaced by otherrifamycin analogs of Formula XII and the macrolide compound 102 can bereplaced by other pharmacophores within the macrolide family thatinclude 14-membered ring, 15-membered ring and 16-membered ringmacrolide structures. It will be also apparent to one skilled in the artthat the macrolide structure can be linked at another position such asthe 6-position, the 9-position and the 11-position. The reaction isperformed in an aprotic solvent catalyzed by an organic or inorganicbase. Examples of solvents suitable for this reaction are DCM, DCE, THF,DMSO, DMF, NMP, acetonitrile or any combination of the above. Examplesof bases are TEA, NMM or other tertiary amines. Under certaincircumstances, excess of 102 can be used as base.

Yet another specific example of the current invention is illustrated byScheme 4, shown in FIG. 7, where25-O-(carbonyl-1-benzy-3H-imidazol-1-ium bromide) rifamycin S (XII, X₃is morpholino) reacts with an oxazolidinone compound of formula 103 togive product of Formula XVI, wherein Ry and Rz are independentlyselected from H or F and Xg is L₃, L₁₁, or L₂₅. It will be apparent toone skilled in the art that the 25-O-(carbonyl-1-benzy-3H-imidazol-1-iumbromide) rifamycin S used herein can be replaced by other rifamycinanalogs of Formula XII and the oxazolidinone compound 103 can bereplaced by other pharmacophores within the oxazolidinone family.Specific variations to the oxazolidinone structure can be made to theC-5 position as indicated on structure 103. These variations have beendescribed in detail by various authors and available in the publicdomain. The reaction is performed in an aprotic solvent catalyzed by anorganic base. Examples of solvents suitable for this reaction are DCM,DCE, THF, DMSO, DMF, NMP, dioxane, acetonitrile or any combination ofthe above. Examples of bases are TEA, NMM, etc. Under certaincircumstances, excess of 103 can be used as base.

Scheme 5a, shown in FIG. 8, illustrates that compounds of Formula XIXaare prepared from 25-O-(prop-2-ynyl-carbamic acid) rifamycin S compoundssuch as XVIIIa through a 1,3-dipolar cycloaddition reaction. Scheme 5b,also shown in FIG. 8, illustrates that compounds of Formula XIXb areprepared from 25-O-(prop-2-enyl carbamic acid rifamycin S compounds suchas XVIIIb through a dipolar cycloaddition reaction.

One specific example for the synthesis of compounds XX is illustrated byScheme 6, shown in FIG. 9, wherein 25-O-(prop-2-ynyl-carbamic acid)rifamycin S (XVIII) reacts with an aryl halide or triflate (105) to giveproducts of Formula XX. The reaction is performed in an aprotic solventwith a palladium catalyst and a phosphine ligand. Examples of solventssuitable for this reaction are DME, THF, dioxane or any combination ofthe above. Examples of bases are NaHCO₃, Na₂CO₃, KHCO₃, K₂CO₃, Cs₂CO₃,etc. Palladium acetate, palladium tetra-kis-triphenyl phosphine, andvarious copper and nickel containing catalysts and a variety of otherpalladium catalysts can be used.

Another specific example of compounds of Formula XXII is illustrated byScheme 7, shown in FIG. 10, where 25-O-(prop-2-enyl-carbamic acid)rifamycin S (XXI) reacts with an aryl halide or triflate (105) in theprescence of palladium to give XXII. It will be apparent to one skilledin the art that compound 105 can be replaced by heterocyclic triflatesor vinyl halides. Examples of solvents suitable for this reaction areDME, THF, dioxane or any combination of the above. Examples of bases areNaHCO₃, Na₂CO₃, KHCO₃, K₂CO₃, Cs₂CO₃, etc. Palladium acetate, palladiumtetra-kis-triphenyl phosphine, nickel containing catalysts and a varietyof other palladium catalysts can be used.

Yet another specific example of the current invention is illustrated byScheme 8a, shown in FIG. 11, in which Formula XXIII reacts with analdehyde or ketone (106) under reductive amination conditions to yieldamine (XXIV). Compound 106 can be an aldehyde (R₃₁=H) or a ketone(R₃₁=alkyl) and Xd is defined by L₂₅ above. Alternatively in Scheme 8b,also shown in FIG. 11, a rifamycin compound of Formula XXV is treatedwith an amine 107 under reductive amination conditions to give acompound of Formula XXIV. R₂₉ can be a hydrogen or alkyl group. R₃₂ andR₃₃ can be selected from the groups defined by R₂ and R₃ above and Xecan be selected from L₂₅ defined above. The reaction is performed in aprotic or aprotic solvent. Examples of solvents suitable for thisreaction are THF, DMSO, DMF, NMP, ethanol, isopropanol, methanol,dioxane, acetonitrile, acetic acid, water or any combination of theabove. Examples of reducing agents are sodium borohydride, sodiumtriacetoxyborohydride, sodium cyanoborohydride, and hydrogen in presenceof a palladium catalyst.

Specific Compositions

The compounds of the current invention may be better understood withreference to the following specific examples, which are representativeof some of the embodiments of the invention, and are not intended tolimit the invention.

All starting material used in these examples are either purchased fromcommercial sources or prepared according to published procedures.Operations involving moisture and/or oxygen sensitive materials areconducted under an atmosphere of nitrogen. Flash chromatography isperformed using silica gel 60 as normal phase adsorbent or C18 silicagel as reverse phase adsorbent. Thin layer chromatography (“TLC”) andpreparative thin layer chromatography (“PTLC”) are performed usingpre-coated plates (E. Merck) and spots are visualized with long-waveultraviolet light followed by an appropriate staining reagent. Nuclearmagnetic resonance (“NMR”) spectra are recorded on a Varian 400 MHzmagnetic resonance spectrometer. ¹H NMR chemical shift are given inparts-per million (δ) downfield from TMS using the residual solventsignal (CHCl₃=δ 7.27, CH₃OH=δ 3.31) as internal standard. ¹H NMRinformation is tabulated in the following format: number of protons,multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet; td, triplet of doublet; dt, doublet of triplet), couplingconstant (s) (J) in hertz. The prefix app is occasionally applied incases where the true signal multiplicity is unresolved and prefix brindicates a broad signal. Electro spray ionization mass spectra arerecorded on a Finnegan LCQ advantage spectrometer.

EXAMPLE 4 25-O-Desacetyl cyclic-21,23-(1-methylethylidene acetal)3-morpholino-rifamycin S

Synthesis: 25-O-desacetyl cyclic-21,23-(1-methylethylideneacetal)-3-morpholino-rifamycin S (5.0 grams, 6.4 mmol) was dissolved inanhydrous methylene chloride (400 ml) under a nitrogen atmosphere. Tothis solution was added 10 eq. (10.4 grams, 64 mmol) carbonyldiimidazolein 5 equal portions over the course of 5 days. After this time thesolution was diluted with ethyl acetate (600 ml) and washed with 1 Maqueous citric acid (500 ml) which was followed by a wash with saturatedsodium chloride (500 ml). The resulting solution was dried with sodiumsulfate, filtered, and evaporated to produce the title compound as adark solid (4.8 grams, 5.5 mmol, 86%) which was used withoutpurification.

EXAMPLE 51-Benzyl-3-(25-O-desacetyl-(carbonyl-cyclic-21,23-(1-methylethylideneacetal) 3-morpholino rifamycin S))-3H-imidazol-1-ium

Synthesis: The compound of Example 4 (500 mg, 0.57 mmol) was dissolvedin anhydrous acetonitrile under a nitrogen atmosphere. To this solutionwas added benzyl bromide (0.135 ml, 1.14 mmol). The resulting solutionwas allowed to stir at room temperature for 24 hours. After this timeadditional benzyl bromide was added (0.135 ml, 1.14 mmol) and theresulting solution was allowed to stir at room temperature for anadditional 24 hours. The solution was diluted with diethyl ether (300ml) and the resulting precipitate, the title compound (480 mg, 0.50mmol, 87%), was collected by filtration and used without furtherpurification.

EXAMPLE 6 25-O-Desacetyl-(1-carbonyl-4-methyl-piperazine) 3-morpholinorifamycin S

Synthesis: The compound of Example 5 (10 mg, 0.01 mmol) was dissolved inmethylene chloride (1 ml) and treated with 1-methyl-piperazine (20 μL,0.2 mmol). The resulting solution was stirred at room temperature for 30minutes. The reaction mixture was diluted with ethyl acetate (3 ml) andwashed with 1 M aqueous citric acid (3 ml) followed by washing withsaturated sodium chloride (3 ml). The resulting solution was dried withsodium sulfate, filtered, and evaporated to produce a dark solid. Thisresidue was taken up in 1:2 (VN) 1 M aqueous HCl/tetrahydrofuran (1 ml)and stirred for 3 hours. After which time the mixture was diluted withethyl acetate (3 ml) and the aqueous layer was removed. This solutionwas vigorously washed with an aqueous solution consisting of 5% (W/V)potassium ferricyanide and 5% (W/V) sodium bicarbonate, which was thenfollowed by multiple washes with saturated sodium chloride. Theresulting solution was dried with sodium sulfate, filtered, andevaporated to produce the title compound. ESI MS m/z (M+H)⁺ 865,(M+H—OCH₃)⁺ 833; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s, 1H), 7.53 (s, 1H),6.37 (d, J=10.9 Hz, 1H), 6.02 (dd, J=6.3 and 16.0 Hz, 1H), 6.06 (d,J=12.1 Hz, 1H), 5.05 (dd, J=5.1 and 12.5 Hz, 1H), 4.97 (d, J=9.8 Hz,1H), 4.88-4.82 (m, 1H), 3.96-3.87 (m, 3H), 3.83-3.82 (m, 1H), 3.77-3.72(m, 2H), 3.57-3.47 (m, 4H), 3.35-3.29 (m, 2H), 3.13-3.07 (m, 1H), 3.10(s, 3H), 2.47-2.29 (m, 1H), 2.26 (s, 1H), δ 2.12 (s, 3H), 1.88-1.79 (m,2H), 1.74 (s, 3H), 1.68-1.58 (m, 1H), 1.04 (d, J=7.0 Hz, 3H), 0.89 (d,J=7.0 Hz, 3H), 0.70 (d, J=6.6 Hz, 3H), 0.20 (d, J=7.0 Hz, 3H).

EXAMPLE 7 25-O-Desacetyl-(1-carbonyl-isobutylamino)3-morpholinorifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using isobutyl amine in place of 1-methyl-piperazine. ESI MS m/z(M+H)⁺ 838, (M+H—OCH₃)⁺ 806; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s, 1H), δ7.52 (s, 1H), 6.39 (d, J=11.0 Hz, 1H), 6.21 (dd, J=6.6 and 16.4 Hz, 1H),6.04 (d, J=12.5 Hz, 1H), 5.06 (dd, J=4.3 and 12.1 Hz, 1H), 4.94 (d,J=10.6 Hz, 1H), 4.84 (t, J=5.9 Hz, 1H), 3.99-3.94 (m, 2H), 3.92-3.87 (m,2H), 3.77-3.72 (m, 2H), 6 3.57-3.52 (m, 2H), 3.54-3.29 (m, 2H),3.17-3.14 (m, 1H), 3.12 (s, 3H), 2.99 (q, J=6.6 Hz, 1H), 2.35-2.32 (m,3H), 2.26 (s, 3H), 2.12 (s, 3H), 2.04-1.98 (m, 1H), 1.87-1.78 (m, 2H),1.74 (s, 3H), 1.04 (d, J=7.0 Hz, 3H), 0.90-0.85 (m, 9H), 0.69 (d, J=7.0Hz, 3H), 0.18 (d, J=7.0 Hz, 3H).

EXAMPLE 8 25-O-Desacetyl-(carbonyl-allylamino) 3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using allyl amine in place of 1-methyl-piperazine. ESI MS m/z(M+H)⁺ 822, (M+H—OCH₃)⁺ 790; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s, 1H),7.52 (s, 1H), 6.39 (d, J=10.6 Hz, 1H), 6.21 (dd, J=6.3 and 15.6 Hz, 1H),6.03 (d, J=13.7 Hz, 1H), 5.86-5.76 (m, 2H), 5.19-5.12 (m, 1H), 5.06 (dd,J=4.3 and 12.1 Hz, 1H), 4.96 (d, J=9.8 Hz, 1H), 4.86 (t, J=6.2 Hz, 1H),3.99-3.95 (m, 2H), 3.92-3.87 (m, 2H), 3.79-3.72 (m, 4H), 3.56-3.52 (m,2H), 3.66-3.29 (m, 2H), 3.18-3.15 (m, 1H), 3.12 (s, 3H), 2.36-2.31 (m,1H), 2.26 (s, 3H), 2.12 (s, 3H), 2.04-1.99 (m, 1H), 1.87-1.78 (m, 2H),1.74 (s, 3H), 1.04 (d, J=7.0 Hz, 3H), 0.89 (d, J=7.0 Hz, 3H), 0.69 (d,J=6.6 Hz, 3H), δ 0.18 (d, J=7.0 Hz, 3H).

EXAMPLE 925-O-Desacetyl-(1-carbonyl-2-(4-methyl-piperazin-1-yl)-ethylamine)3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using 2-(4-methyl-piperazin-1-yl)-ethylamine in place of1-methyl-piperazine. ESI MS m/z (M+H)⁺ 908; ¹H NMR (400 MHz, CDCl₃) δ13.25 (s, 1H), 7.53 (s, 1H), δ 3.38 (d, J=10.6 Hz, 1H), 6.20 (dd, J=6.3and 16.0 Hz, 1H), 6.05 (d, J=12.1 Hz, 1H), 5.06 (dd, J=4.7 and 12.1 Hz,1H), 4.92 (d, J=10.2 Hz, 1H), 3.97-3.86 (m, 5H), 3.77-3.72 (m, 2H),3.57-3.52 (m, 3H), 3.34-3.24 (m, 4H), 3.18-3.15 (m, 1H), 3.10 (s, 3H),2.59-2.42 (m, 8H), 2.37 (s, 3H), 2.25 (s, 3H), 2.12 (s, 3H), 1.86-1.79(m, 3H), 1.74 (s, 3H), 1.68-1.56 (m, 1H), 1.04 (d, J=7.0 Hz, 3H), 0.89(d, J=7.0 Hz, 3H), 0.69 (d, J=6.6 Hz, 3H), 0.18 (d, J=7.0 Hz, 3H).

EXAMPLE 10 25-O-Desacetyl-(1-carbonyl-2-diethylamine) 3-morpholinorifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using diethylamine in place of 1-methyl-piperazine. ESI MS m/z(M+H)⁺ 838, (M+H—OCH₃)⁺ 806; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s, 1H), δ7.51 (s, 1H), 6.41 (d, J=10.8 Hz, 1H), 6.23 (dd, J=6.3 and 15.6 Hz, 1H),6.03 (d, J=14.0 Hz, 1H), 5.05 (dd, J=4.3 and 12.1 Hz, 1H), 5.01 (d,J=10.2 Hz, 1H), 3.99-3.97 (m, 1H), 3.92-3.87 (m, 2H), δ 3.77-3.72 (m,2H), 3.56-3.52 (m, 3H), 3.39-3.26 (m, 4H), 3.19-3.14 (m, 2H), δ 3.10 (s,3H), 2.37-2.31 (m, 1H), 2.25 (s, 3H), 2.12 (s, 3H), 1.91-1.79 (m, 2H),1.75 (s, 3H), 1.70-1.59 (m, 1H), 1.09 (t, J=6.3 Hz, 6H), 1.04 (d, J=7.0Hz, 3H), 0.89 (d, J=7.0 Hz, 3H), 0.72 (d, J=6.6 Hz, 3H), 0.21 (d, J=7.0Hz, 3H).

EXAMPLE 11 25-O-Desacetyl-(1-carbonyl-3-imidazol-1-yl-propylamine)3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using 3-imidazol-1-yl-propylamine in place of1-methyl-piperazine. ESI MS m/z (M+H)⁺ 890; ¹H NMR (400 MHz, CDCl₃) δ13.25 (s, 1H), δ 7.72-7.70 (m, 1H), δ 7.56-7.52 (m, 1H), 7.48 (s, 1H),7.06 (s, 1H), 6.36 (d, J=10.9 Hz, 1H), 6.17 (dd, J=6.6 and 16.0 Hz, 1H),6.04 (d, J=12.1 Hz, 1H), 5.06 (dd, J=5.0 and 12.1 Hz, 1H), 4.96-4.90 (m,2H), 4.01-3.88 (m, 5H), 3.78-3.70 (m, 3H), 3.57-3.50 (m, 2H), 3.34-3.29(m, 2H), 3.21-3.09 (m, 3H), 3.11 (s, 3H), 2.42-2.30 (m, 1H), 2.27 (s,3H), 2.01-1.94 (m, 2H), 1.85-1.79 (m, 1H), 1.74 (s, 3H), 1.04 (d, J=7.0Hz, 3H), 0.94-0.83 (m, 5H), 0.68 (d, J=6.6 Hz, 3H), 0.19 (d, J=6.6 Hz,3H).

EXAMPLE 12 25-O-Desacetyl-(1-carbonyl-1-(4-fluorophenyl)-piperazine)3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using 4-(fluorophenyl)-piperazine in place of1-methyl-piperazine. ESI MS m/z (M+H)⁺ 945, (M+H—OCH₃)⁺ 913; ¹H NMR (400MHz, CDCl₃) δ 13.25 (s, 1H), 7.52 (s, 1H), 7.22-7.14 (m, 1H), 7.01-6.85(m, 5H), δ 6.36 (d, J=10.7 Hz, 1H), 6.19-6.13 (m, 1H), 6.04 (d, J=14.4Hz, 1H), 5.08-5.03 (m, 1H), 4.99-4.97 (d, J=9.8 Hz, 1H), 4.84-4.76 (m,1H), δ 3.96-3.87 (m, 1H), δ 3.78-3.70 (m, 2H), 3.66-3.59 (m, 3H),3.56-3.47 (m, 3H), 3.33-3.27 (m, 2H), 3.10 (s, 3H), 3.10-2.94 (m, 2H),2.40-2.30 (m, 1H), 2.24 (s, 3H), 2.10 (s, 3H), 1.89-1.77 (m, 3H), 1.73(s, 3H), 1.05-1.02 (m, 3H), 0.88-0.85 (m, 3H), 0.72-0.69 (m, 3H),0.21-0.18 (m, 3H).

EXAMPLE 13 25-O-Desacetyl-(carbonyl-1-(3-trifluoromethylbenzylamino))3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using 3-(trifluoromethylphenyl)-piperazine in place of1-methyl-piperazine. ESI MS m/z (M+H)⁺ 940, (M+H—OCH₃)⁺ 908; ¹H NMR (400MHz, CDCl₃) δ 13.25 (s, 1H), 7.52-7.50 (m, 3H), 7.45-7.44 (m, 2H), 6.39(d, J=10.9 Hz, 1H), 6.19 (dd, J=6.3 and 15.6 Hz, 1H), 6.03 (d, J=12.1Hz, 1H), 5.25 (t, J=6.0 Hz, 1H), 5.04 (dd, J=4.7 and 12.1 Hz, 1H), 4.98(d, J=9.4 Hz, 1H), 4.48-4.33 (m, 2H), 3.39-3.87 (m, 3H), 3.76-3.71 (m,2H), 3.57-3.49 (m, 3H), 3.34-3.29 (m, 2H), 3.16-3.13 (m, 1H), 3.03 (s,3H), 2.38-2.31 (m, 1H), 2.25 (s, 3H), 2.12 (s, 3H), 1.88-1.79 (m, 3H),1.74 (s, 3H), 1.04 (d, J=7.0 Hz, 3H), 0.89 (d, J=7.0 Hz, 3H), 0.69 (d,J=6.6 Hz, 3H), 0.18 (d, J=7.4 Hz, 3H).

EXAMPLE 14 25-O-Desacetyl-(carbonyl-1-pyrrolidino) 3-morpholinorifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using pyrrolidine in place of 1-methyl-piperazine. ESI MS m/z(M+H)⁺ 836, (M+H—OCH₃)⁺ 804; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s, 1H),7.52 (s, 1H), 6.39 (d, J=10.9 Hz, 1H), 6.22 (dd, J=6.6 and 15.6 Hz, 1H),6.03 (d, J=12.1 Hz, 1H), 5.05 (dd, J=4.3 and 12.1 Hz, 1H), 4.97 (d,J=9.4 Hz, 1H), 3.98-3.96 (m, 2H), 3.92-3.87 (m, 2H), 3.77-3.72 (m, 2H),3.57-3.51 (m, 4H), 3.40-3.27 (m, 6H), 3.16-3.14 (m, 1H), 3.10 (s, 3H),2.36-2.31 (m, 1H), 2.26 (s, 3H), 2.12 (s, 3H), 1.91-1.78 (m, 3H), 1.74(s, 3H), δ 1.27-1.24 (m, 4H), 1.04 (d, J=7.0 Hz, 3H), 0.89 (d, J=7.0 Hz,3H), 0.71 (d, J=7.0 Hz, 3H), 0.18 (d, J=7.0 Hz, 3H).

EXAMPLE 15 25-O-Desacetyl (carbonyl-benzyl) 3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using benzylamine in place of 1-methyl-piperazine. ESI MS m/z(M+H)⁺ 872, (M+H—OCH₃)⁺ 840; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s, 1H), δ7.52 (s, 1H), δ 7.33-7.23 (m, SH), δ 6.39 (d, J=10.6 Hz, 1H), δ 6.21(dd, J=5.5 and 14.8 Hz, 1H), δ 6.02 (d, J=12.1 Hz, 1H), δ 5.13 (t, J=5.8Hz, 1H), δ 5.04 (dd, J=3.9 and 11.7 Hz, 1H), δ 4.98 (d, J=10.2 Hz, 1H),δ 4.33 (d, J=6.3 Hz, 2H), δ 3.99-3.87 (m, 3H), δ 3.76-3.71 (m, 2H), δ3.56-3.47 (m, 3H), δ 3.34-3.28 (m, 2H), δ 3.18-3.16 (m, 1H), δ 3.05 (s,3H), δ 2.36-2.31 (m, 1H), δ 2.26 (s, 3H), δ 2.12 (s, 3H), δ 1.88-1.80(m, 1H), δ 1.73 (s, 3H), δ 1.04 (d, J=6.3 Hz, 3H), δ 0.89 (d, J=7.0 Hz,3H), δ 0.68 (d, J=7.0 Hz, 3H), δ 0.18 (d, J=7.0 Hz, 3H).

EXAMPLE 1625-O-Desacetyl-(4-carbonyl-1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S

Synthesis: 1-Benzyl-3-(25-O-carbonyl-3-morpholino rifamycin Scyclic-21,23-(1-methylethylidene acetal))-3H-imidazol-1-ium, (10 mg,0.010 mmol) was dissolved in methylene chloride (1 ml). To this wasadded1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid (10 mg, 0.030 mmol) and N-methylmorpholine (6 ul, 0.050 mmol). Theresulting solution was stirred at room temperature for 30 minutes. Thereaction mixture was diluted with ethyl acetate (3 ml) and washed with 1M aqueous citric acid (3 ml) followed by washing with brine (3 ml). Theresulting solution was dried with sodium sulfate, filtered, andevaporated to produce a dark solid. This residue was taken up in 1:2(V/V) 1 M aqueous HCl/tetrahydrofuran (1 ml) and stirred for 3 hours.After which time the mixture was diluted with ethyl acetate (3 ml) andthe aqueous layer was removed. This solution was vigorously washed withan aqueous solution consisting of 5% (WN) potassium ferricyanide and 5%(W/V) sodium bicarbonate, which was then followed by multiple washeswith brine. The resulting solution was dried with sodium sulfate,filtered, and evaporated. The residue was purified by silica gel columnchromatography (step gradient; (99.9% EtOAc/0.01% HOAc) to (89.9%EtOAc/10% MeOH/0.01% HOAc) to (49.9% EtOAc/50% MeOH/0.01% HOAc) toproduce the title compound. ESI MS m/z (M+H)⁺ 1096; ¹H NMR (400 MHz,CDCl₃) δ 13.25 (s, 1H), 8.79 (s, 1H), 8.06 (d, J=12.5 Hz, 1H), 7.56 (s,1H), 6.36 (d, J=10.6 Hz, 1H), 6.16 (dd, J=6.6 and 16.4 Hz, 1H), 6.07 (d,J=10.9 Hz, 1H), 5.09 (dd, J=5.1 and 13.7 Hz, 1H), 5.02 (d, J=10.2 Hz,1H), 3.95-3.87 (m, 3H), 3.77-3.62 (m, 4H), 3.58-3.50 (m, 3H), 3.35-3.22(m, 5H), 3.12 (s, 3H), 2.38-2.33 (m, 1H), 2.27 (s, 3H), 2.14-2.12 (m,2H), 2.09 (s, 3H), 1.88-1.79 (m, 1H), 1.74 (s, 3H), 1.05 (d, J=7.0 Hz,3H), 0.89-0.78 (m, 7H), 0.72 (d, J=6.6 Hz, 3H), 0.24 (d, J=7.0 Hz, 3H).

EXAMPLE 1725-O-Desacetyl-(8-chloro-1-cyclopropyl-7-[4-(1-carbonyl)-piperazin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 16above, using8-chloro-1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid in place of1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid. ESI MS m/z (M+H)⁺ 1130, (M+H—OCH₃)⁺ 1098; ¹H NMR (400 MHz, CDCl₃)δ 13.25 (s, 1H), 8.88 (s, 1H), 7.96 (d, J=12.9 Hz, 1H), 7.53 (s, 1H),7.22-7.16 (m, 1H), 6.37 (d, J=10.9 Hz, 1H), 6.22-6.13 (m, 1H), 6.04 (dd,J=11.5 and 22.0 Hz, 1H), 5.18 (t, J=6.8 Hz, 1H), 5.11-5.02 (m, 1H), δ4.97-4.93 (m, 1H), 4.40-4.25 (m, 2H), 3.96-3.85 (m, 3H), 3.84-3.71 (m,3H), 3.66-3.62 (m, 1H), 3.57-3.43 (m, 3H), 3.34-3.29 (m, 2H), 3.15 (s,1.5H), 63.04 (s, 1.5H), 2.38-2.31 (m, 1H), 2.26 (s, 1.5H), 2.25 (s,1.5H), 2.12 (s, 1.5H), 2.01-1.92 (m, 1H), 1.84-1.79 (m, 1H), 1.75 (s,1.5H), 1.73 (s, 1.5H), 1.68-1.61 (m, 1H), 1.82-1.23 (m, 5H), 1.06-0.87(m, 5H), 0.71-0.67 (m, 3H), 0.20-0.17 (m, 3H).

EXAMPLE 18 25-O-Desacetyl-(1-carbonyl-(2-pyridin-2-yl-ethylamine))3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using 2-pyridin-2-yl-ethylamine in place of 1-methyl-piperazine.ESI MS m/z (M+H)⁺ 887, (M+H—OCH₃)⁺ 885; ¹H NMR (400 MHz, CDCl₃) δ 13.25(s, 1H), 8.52 (d, J=6.3 Hz, 1H), 7.61 (t, J=7.4 Hz, 1H), 7.51 (s, 1H),7.17-7.13 (m, 2H), 6.39 (d, J=11.3 Hz, 1H), 6.21 (dd, J=6.6 and 16.0 Hz,1H), 6.00 (d, J=12.5 Hz, 1H), 5.59 (t, J=5.6 Hz, 1H), 5.02 (dd, J=4.7and 12.5 Hz, 1H), 4.90-4.89 m, 1H), 3.97-3.87 (m, 3H), 3.76-3.72 (m,2H), 3.61-3.49 (m, 3H), 3.33-3.29 (m, 2H), 3.15-3.12 (m, 1H), δ 3.04 (s,3H), 0.89 (d, J=7.0 Hz, 3H), 3.00-2.95 (m, 2H), 2.37-2.31 (m, 1H), 2.25(s, 3H), 2.12 (s, 3H), 2.1-1.99 (m, 1H), 1.86-1.81 (m, 1H), 1.74 (s,3H), 1.04 (d, J=7.0 Hz, 3H), 0.89 (d, J=7.0 Hz, 3H), 0.66 (d, J=6.6 Hz,3H), 0.89 (d, J=7.0 Hz, 3H).

EXAMPLE 19 25-O-Desacetyl-(1-carbonyl-2-thiophen-2-yl-ethylamine)3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using 2-pyridin-2-yl-ethylamine in place of 1-methyl-piperazine.ESI MS m/z (M+H)⁺ 892, (M+H—OCH₃)⁺ 860; ¹H NMR (400 MHz, CDCl₃) δ 13.25(s, 1H), 7.52 (s, 1H), 7.15 (d, J=5.9 Hz, 1H), 6.96-6.92 (m, 1H), 6.80(d, J=3.1 Hz, 1H), 6.39 (d, J=11.0 Hz, 1H), 6.24-6.18 (m, 1H), 6.03 (d,J=12.1 Hz, 1H), 5.04 (dd, J=4.7 and 12.5 Hz, 1H), 3.97-3.85 (m, 3H),3.76-3.71 (m, 3H), 3.56-3.52 (m, 2H), 3.48-3.39 (d, J=7.0 Hz, 2H),3.34-3.29 (m, 1H), 3.17-3.13 (m, 1H), 3.11 (s, 3H), 3.08-2.97 (m, 4H),2.40-2.30 (m, 1H), 2.26 (s, 3H), 2.17-2.15 (m, 1H), 2.12 (s, 3H),2.04-2.00 (m, 1H), 1.85-1.79 (m, 1H), 1.75 (s, 3H), 1.05 (d, J=6.6 Hz,3H), 0.89 (d, J=6.6 Hz, 3H), 0.67 (d, J=6.6 Hz, 3H), δ 0.18 (d, J=7.0Hz, 3H).

EXAMPLE 20 25-O-Desacetyl-(1-carbonyl-2-aminoethanol) 3-morpholinorifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using 2-ethanolamine in place of 1-methyl-piperazine. ESI MS m/z(M+H)⁺ 826, (M+H—OCH₃)⁺ 794; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s, 1H),7.52 (s, 1H), 3.39 (d, J=10.6 Hz, 1H), 6.19 (dd, J=6.6 and 14.9 Hz, 1H),6.03 (d, J=12.5 Hz, 2H), 5.23 (m, 1H), 5.06 (dd, J=4.7 and 12.1 Hz, 1H),4.95 (d, J=10.6 Hz, 1H), 4.69 (m, 1H), 3.97-3.87 (m, 3H), 3.77-3.69 (m,5H), 3.56-3.52 (m, 2H), 3.36-3.25 (m, 2H), 3.20-3.15 (m, 1H), δ 3.13 (s,3H), 2.37-2.30 (m, 1H), 2.26 (s, 3H), 2.12 (s, 3H), 2.01-1.92 (m, 1H),1.85-1.79 (m, 2H), 174 (s, 3H), 1.03 (d, J=7.0 Hz, 3H), 0.89 (d, J=7.0Hz, 3H), 0.69 (d, J=6.6 Hz, 3H), 0.18 (d, J=7.0 Hz, 3H).

EXAMPLE 21 25-O-Desacetyl-(carbonyl-methylamino) 3-morpholino rifamycinS

Synthesis: The title compound was prepared as described in Example 6above, using methylamine in place of 1-methyl-piperazine. ESI MS m/z(M+H)⁺ 796, (M+H—OCH₃)⁺ 764; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s, 1H),7.16 (s, 1H), 6.40 (d, J=11.0 Hz, 1H), 6.21 (dd, J=7.0 and 16.4 Hz, 1H),6.04 (d, J=12.1 Hz, 1H), 5.05 (dd, J=5.7 and 13.3 Hz, 1H), 4.95 (d,J=9.8 Hz, 1H), 3.98-3.87 (m, 3H), 3.76-3.71 (m, 3H), 3.56-3.51 (m, 2H),3.34-3.29 (m, 2H), 3.18-3.15 (m, 1H), 3.11 (s, 3H), 2.79-2.78 (d, J=4.7Hz, 3H), 2.38-2.32 (m, 3H), 2.26 (s, 3H), 2.18-2.14 (m, 1H), 2.12 (s,3H), 2.04-1.97 (m, 1H), 1.86-1.78 (m, 1H), 1.74 (s, 3H), 1.04 (d, J=7.0Hz, 3H), 0.89 (d, J=7.0 Hz, 3H), 0.68 (d, J=7.0 Hz, 3H), 0.18 (d, J=7.0Hz, 3H).

EXAMPLE 22 25-O-Desacetyl-(carbonyl-4-chlorobenzyl) 3-morpholinorifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using 4-chlorobenzylamine in place of 1-methyl-piperazine. ¹H NMR(400 MHz, CDCl₃) δ 7.53 (s, 1H), δ 7.38-7.17 (m, 5H), 6.38 (d, J=10.6Hz, 1H), 6.28-6.17 (m, 1H), 6.03 (d, J=12.1 Hz, 1H), δ 5.17-5.14 (m,1H), 5.04 (dd, J=4.3 and 12.1 Hz, 1H), 4.96 (d, J=10.1 Hz, 1H), 4.29 (d,J=6.3 Hz, 2H), 3.96-3.70 (m, 4H), 3.57-3.28 (m, 4H), 3.23-3.11 (m, 2H),3.04-3.01 (m, 4H), 2.44-2.30 (m, 1H), 2.25 (s, 3H), 2.18-2.15 (m, 2H),2.12 (s, 3H), 2.02-2.00 (m, 1H), 1.74 (s, 3H), 1.03 (d, J=5.8 Hz, 3H),0.89 (d, J=6.3 Hz, 3H), 0.67 (d, J=5.5 Hz, 3H), 0.18 (d, J=6.6 Hz, 3H);ESI MS m/z 906.0 (M+H)⁺.

EXAMPLE 23 25 -O-Desacetyl-(carbonyl-naphthalen-1-ylmethyl-amino)3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using naphthyl-1-yl methyl in place of 1-methyl-piperazine. ESIMS m/z (M+H)⁺ 922, (M+H—OCH₃)⁺ 890; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s,1H), 8.00-7.98 (m, 1H), 7.90-7.80 (m, 2H), 7.56-7.50 (m, 2H), 7.46-7.40(m, 2H), 6.39 (d, J=11.3 Hz, 1H), 6.27-6.18 (m, 1H), 6.01 (d, J=11.0 Hz,1H), 5.26-5.17 (m, 1H), 5.11-5.08 (m, 1H), 5.03-4.89 (m, 1H), 4.85-4.80(m, 2H), 3.97-3.86 (m, 3H), 3.77-3.72 (m, 3H), 3.56-3.48 (m, 2H),3.40-3.28 (m, 2H), 3.25-3.17 (m, 1H), 3.05 (s, 3H), 2.40-2.30 (m, 1H),2.26 (s, 3H), 2.12 (s, 3H), 2.09-2.02 (m, 1H), 1.88-1.84 (m, 2H), 1.73(s, 3H), 1.06 (d, J=6.6 Hz, 3H), 0.88 (d, J=6.3 Hz, 3H), 0.64 (d, J=6.6Hz, 3H), 0.17 (d, J=6.6 Hz, 3H).

EXAMPLE 24 25-O-Desacetyl-(carbonyl-3-phenylpropylamino) 3-morpholinorifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using 3-phenyl-propylamine in place of 1-methyl-piperazine. ESIMS m/z (M+H)⁺ 900, (M+H—OCH₃)⁺ 878; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s,1H), δ 7.52 (s, 1H), δ 7.33-7.27 (m, 2H), δ 7.20-7.13 (m, 3H), δ 6.39(d, J=10.2 Hz, 1H), δ 6.20 (dd, J=7.4 and 15.0 Hz, 1H), δ 6.04 (d,J=11.7 Hz, 1H), δ 5.05 (d, J=14.1 Hz, 1H), δ 4.93 (d, J=9.0 Hz, 1H), δ4.82-4.78 (m, 2H), δ 3.97-3.86 (m, 3H), δ 3.78-3.70 (m, 3H), δ 3.57-3.50(m, 2H), δ 3.40-3.28 (m, 2H), δ 3.21-3.16 (m, 1H), δ 3.11 (s, 3H), δ2.67-2.59 (m, 2H), δ 2.37-2.29 (m, 1H), δ 2.25 (s, 3H), δ 2.11 (s, 3H),δ 2.08-2.05 (m, 3H), δ 1.73 (s, 3H), δ 1.03 (d, J=5.8 Hz, 3H), δ 0.89(d, J=6.3 Hz, 3H), δ 0.67 (d, J=5.5 Hz, 3H), δ 0.18 (d, J=6.6 Hz, 3H).

EXAMPLE 25 25-O-Desacetyl-(carbonyl-3-phenylethylamino) 3-morpholinorifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using 3-phenethylamine in place of 1-methyl-piperazine. ESI MSm/z (M+H)⁺ 886, (M+H—OCH₃)⁺ 854; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s,1H), δ 7.53 (s, 1H), 7.31-7.26 (m, 2H), 7.23-7.22 (d, J=8.2 Hz, 1H),7.15 (d, J=7.4 Hz, 2H), 6.39 (d, J=10.5 Hz, 1H), 6.21 (dd, J=6.3 and16.0 Hz, 1H), 6.02 (d, J=12.1 Hz, 1H), 5.02 (dd, J=4.7 and 12.5 Hz, 1H),4.92 (d, J=9.8 Hz, 1H), 4.08-4.77 (m, 2H), 3.97-3.87 (m, 3H), 3.78-3.71(m, 3H), 3.56-3.51 (m, 2H), 3.48-3.41 (m, 2H), 3.14-3.11 (m, 1H), 3.07(s, 3H), 2.82-2.74 (m, 2H), 2.38-2.29 (m, 1H), 2.25 (s, 3H), 2.12 (s,3H), 1.86-1.79 (m, 2H), 1.74 (s, 3H), 1.57-1.52 (m, 1H), 1.05 (d, J=7.0Hz, 3H), 0.89 (d, J=7.0 Hz, 3H), 0.65 (d, J=6.6 Hz, 3H), 0.17 (d, J=7.0Hz, 3H).

EXAMPLE 26 25-O-Desacetyl-(carbonyl-4-methoxybenzylamino) 3-morpholinorifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using 4-methoxybenzylamine in place of 1-methyl-piperazine. ESIMS m/z (M+H)⁺ 902, (M+H—OCH₃)⁺ 870; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s,1H), 7.53 (s, 1H), 7.17 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 6.39(d, J=10.6 Hz, 1H), 6.21 (dd, J=6.3 and 15.6 Hz, 1H), 6.03 (d, J=12.1Hz, 1H), 5.09-5.02 (m, 1H), 4.97 (d, J=9.8 Hz, 1H), 4.26 (d, J=5.9 Hz,1H), 4.00-3.87 (m, 3H), 3.82-3.71 (m, 3H), 3.78 (s, 3H), 3.56-3.51 (m,2H), 3.34-3.29 (m, 2H), 3.17-3.10 (m, 2H), 3.05 (s, 3H), 2.43-2.30 (m,1H), 2.26 (s, 3H), 2.23-2.71 (m, 2H), 2.12 (s, 3H), 1.85-1.80 (m, 3H),1.73 (s, 3H), 1.62-1.56 (m, 1H), 1.04 (d, J=6.6 Hz, 3H), 0.89 (d, J=7.0Hz, 3H), 0.67 (d, J=6.6 Hz, 3H), 0.18 (d, J=7.0 Hz, 3H).

EXAMPLE 27 25-O-Desacetyl-((2-Amino-ethyl)-carbamic acid6-[6-(4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-oxacyclotetradec-4-yloxy]-4-methoxy-2,4-dimethyl-tetrahydro-pyran-3-ylester) 3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using (2-Amino-ethyl)-carbamic acid6-[6-(4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-oxacyclotetradec-4-yloxy]-4-methoxy-2,4-dimethyl-tetrahydro-pyran-3-ylester in place of 1-methyl-piperazine. ESI MS m/z (M+H)⁺ 1598,(M+H—OCH₃)⁺ 1566; ¹H NMR (400 MHz, CDCl₃) δ 7.52 (s, 1H), 6.40 (d,J=14.4 Hz, 1H), 7.23-6.16 (m, 1H), 6.01 (d, J=14.0 Hz, 1H), 5.07-4.20(complex pattern , 8H), 4.00-2.86 (complex pattern), 2.60-1.41 (complexpattern), 1.38-0.65 (complex pattern), 0.16 (d, J=7.0 Hz, 3H).

EXAMPLE 2825-O-Desacetyl-(carbonyl-1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid in place of 1-methyl-piperazine. ESI MS m/z (M+H)⁺ 1140,(M+H—OCH₃)⁺ 1108; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s, 1H), 8.77 (s, 1H),7.84 (d, J=12.1 Hz, 1H), 7.48 (s, 1H), 7.16-7.10 (m, 1H), 6.31 (d, J=7.8Hz, 1H), 6.16-6.13 (m, 1H), 6.05-5.98 (m, 1H), 5.04-4.95 (m, 2H),4.81-4.70 (m, 1H), 4.40-4.22 (m, 1H), 3.97-3.82 (m, 4H), 3.74-3.63 (m,2H), 3.66 (s, 3H), 3.52-3.36 (m, 3H), 3.28-3.21 (m, 2H), 3.12-3.03 (m,3H), 2.33-2.67 (m, 1H), 2.21 (s, 3H), 2.06 (s, 3H), 1.87-1.74 (m, 2H),1.68 (s, 3H), 1.30-1.24 (m, 3H), 1.19 (s, 3H), 1.17-1.36 (m, 1H),1.01-0.99 (m, 4H), 0.94-0.91 (m, 1H), 0.85-0.28 (m, 5H), 0.67 (d, J=6.6Hz, 3H), 0.20-0.18 (m, 3H).

EXAMPLE 2925-O-Desacetyl-(carbonyl-2-ethyl-octahydro-pyrrolo[3,4-c]pyrrole)3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using 2-ethyl-octahydro-pyrrolo[3,4-c]pyrrole in place of1-methyl-piperazine. ESI MS m/z (M+H)⁺ 905, (M+H—OCH₃)⁺ 873; ¹H NMR (400MHz, CDCl₃) δ 13.25 (s, 1H), 7.53 (s, 1H), 6.98 (s, 1H), 6.39 (d, J=10.9Hz, 1H), 6.21 (dd, J=6.3 and 16.4 Hz, 1H), 6.04 (d, J=12.5 Hz, 1H), 5.05(dd, J=4.7 and 12.1 Hz, 1H), 4.96 (d, J=9.8 Hz, 1H), 3.97-3.87 (m, 3H),3.77-3.70 (m, 2H), 3.59-3.47 (m, 3H), 3.38-3.27 (m, 2H), 3.16-3.09 (m,3H), 2.96-2.74 (m, 3H), 3.97-3.87 (m, 4H), 2.55-2.30 (m, 4H), 2.25 (s,3H), 2.12 (s, 3H), 1.90-1.81 (m, 4H), 1.74 (s, 3H), 1.13 (m, 3H), 1.04(d, J=7.0 Hz, 3H), 0.89 (d, J=7.0 Hz, 3H), 0.70 (d, J=6.6 Hz, 3H), 0.20(d, J=7.4 Hz, 3H).

EXAMPLE 30 25-O-Desacetyl-(carbonyl-N,N-dimethylethylenediamine)3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using N,N-dimethylethylenediamine in place of1-methyl-piperazine. ESI MS m/z (M+H)⁺ 853, (M+H—OCH₃)⁺ 821; ¹H NMR (400MHz, CDCl₃) δ 13.25 (s, 1H), 7.52 (s, 1H), 6.98 (s, 1H), 6.39 (d, J=10.9Hz, 1H), 6.21 (dd, J=6.3 and 15.6 Hz, 1H), 6.04 (d, J=12.1 Hz, 1H), 5.39(br, 1H), 5.06 (dd, J=4.3 and 12.1 Hz, 1H), 4.93 (d, J=10.2 Hz, 1H),3.96 (d, J=9.0 Hz, 1H), 3.92-3.87 (m, 3H), 3.68-3.70 (m, 2H), 3.59-3.51(m, 3H), 3.35-3.29 (m, 2H), 3.24 (q, J=5.5 Hz 2H), 3.17 (d, J=9.8 Hz,1H), 3.12 (s, 3H), 2.45-2.39 (m, 2H), 2.37-2.32 (m, 2H), 2.25 (s, 3H),2.23 (s, 3H), 2.23-2.20 (m, 1H), 1.88-1.75 (m, 4H), 1.74 (s, 3H),1.61-1.55 (m, 3H), 1.43 (s, 3H), 1.04 (d, J=7.0 Hz, 3H), 1.04 (d, J=6.6Hz, 3H), 0.69 (d, J=6.6 Hz, 3H), 0.18 (d, J=7.0 Hz, 3H).

EXAMPLE 3125-O-Desacetyl-(carbonyl-2-(1-methyl-pyrrolidin-2-yl)-ethylamine)3-morpholino rifamycin S

Synthesis: The title compound was prepared as described above using2-(1-methyl-pyrrolidin-2-yl)-ethylamine. ESI MS m/z (M+H)⁺ 893,(M+H—OCH₃)⁺ 861; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s, 1H), 7.51 (s, 1H),6.97 (s, 0.5H), 6.40 (d, J=10.6 Hz, 1H), 6.22 (dd, J=5.9 and 15.6 Hz,1H), 6.04 (d, J=12.1 Hz, 1H), 5.05 (dd, J=4.3 and 12.1 Hz, 1H), 6.22(dd, J=5.9 and 15.6 Hz, 1H), 4.92 (d, J=9.4 Hz, 1H), 4.90 (br, 1H), 6.22(dd, J=5.9 and 15.6 Hz, 1H), 3.96 (d, J=9.8 Hz, 1H), 3.92-3.87 (m, 2H),3.76-3.71 (m, 2H), 3.57-3.49 (m, 3H), 3.34-3.29 (m, 2H), 3.27-3.20 (m,2H), 3.10 (s, 3H), 2.35-2.30 (m, 2H), 2.25 (s, 3H), 2.11 (s, 3H),1.86-1.77 (m, 2H), 1.74 (s, 3H), 1.63-1.53 (m, 4H), 1.42 (s, 3H), 1.04(d, J=7.0 Hz, 3H), 0.89 (d, J=7.0 Hz, 3H), 0.68 (d, J=7.0 Hz, 3H), 0.18(d, J=7.0 Hz, 3H).

EXAMPLE 32 25-O-Desacetyl-(carbonyl-2-Pyrrolidin-1-yl-ethylamine)3-morpholino rifamycin S

Synthesis: The title compound was prepared as described above, using2-pyrrolidin-1-yl-ethylamine in place of 1-methyl-piperazine. ESI MS m/z(M+H)⁺ 879, (M+H—OCH₃)⁺ 847; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s, 1H),7.51 (s, 1H), 6.98 (s, 0.5H), 7.62 (d, J=8.0 Hz, 1H), 6.39 (d, J=10.9Hz, 1H), 6.21 (dd, J=6.6 and 16.2 Hz, 1H), 6.063 (dd, J=1.4 and 12.3 Hz,1H), 5.06 (dd, J=4.5 and 12.5 Hz, 1H), 4.93 (d, J=10.2 Hz, 1H),3.97-3.87 (m, 3H), 3.77-3.71 (m, 2H), 3.58-3.52 (m, 2H), 3.34-3.27 (m,3H), 3.18-3.16 (m, 1H), 3.11 (s, 3H), 2.64-2.47 (m, 5H), 2.37-2.31 (m,1H), 2.25 (s, 3H), 2.12 (s, 3H), 1.72 (s, 3H), 1.04 (d, J=7.0 Hz, 3H),0.89 (d, J=7.0 Hz, 3H), 0.68 (d, J=6.8 Hz, 3H), 0.18 (d, J=7.0 Hz, 3H).

EXAMPLE 33 25-O-Desacetyl-(carbonyl-1-benzyl-piperidin-4-ylamine)3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using 1-benzyl-piperidin-4-ylamine in place of1-methyl-piperazine. ESI MS m/z (M+H)⁺ 955, (M+H—OCH₃)⁺ 923; ¹H NMR (400MHz, CDCl₃) δ 13.25 (s, 1H), 7.52 (s, 1H), 7.35-7.30 (m, 5H), 6.39 (d,J=10.6 Hz, 1H), 6.20 (d, J=6.3 and 16.0 Hz, 1H), 5.04 (dd, J=4.3 and12.1 Hz, 1H), 4.90 (d, J=10.2 Hz, 1H), 4.79-4.77 (m, 1H), 3.96-3.85 (m,3H), 3.76-3.71 (m, 2H), 3.57-3.48 (m, 4H), 3.34-3.29 (m, 2H), 3.15-3.11(m, 1H), 3.10 (s, 3H), δ 3.06-3.04 (m, 1H), δ 2.92-2.80 (m, 1H),2.36-2.30 (m, 1H), 2.25 (s, 3H), 2.12 (s, 3H), 1.96-1.80 (m, 3H), 1.74(s, 3H), 1.62-1.56 (s, 1H), 1.03 (d, J=7.0 Hz, 3H), 0.88 (d, J=7.0 Hz,3H), 0.67 (d, J=7.0 Hz, 3H), 0.17 (d, J=7.0 Hz, 3H).

EXAMPLE 34 25-O-Desacetyl-(carbonyl-4-phenyl-butylamine) 3-morpholinorifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using 4-phenyl-butylamine in place of 1-methyl-piperazine. ESI MSm/z (M+H)⁺ 914, (M+H—OCH₃)⁺ 882; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s,1H), 7.52 (s, 1H), 7.28-7.24 (m, 2H), 7.19-7.12 (m, 3H), 6.39 (d, J=10.6Hz, 1H), 6.20 (dd, J=6.3 and 15.6 Hz, 1H), 6.03 (d, J=12.1 Hz, 1H), 5.04(dd, J=4.7 and 12.5 Hz, 1H), 4.92 (d, J=9.8 Hz, 1H), 4.82 (d, J=3.5 Hz,1H), 4.77-4.76 (m, 1H), 3.96 (d, J=9.4 Hz, 1H), 3.92-3.67 (m, 2H),3.76-3.71 (m, 2H), 3.56-3.50 (m, 3H), 3.34-3.29 (m, 2H), 3.21-3.12 (m,2H), 3.08 (s, 3H), 2.61 (t, J=7.0 Hz, 2H), 2.37-2.31 (m, 2H), 2.25 (s,3H), 2.12 (s, 3H), 1.91-1.78 (m, 3H), 1.75 (s, 3H), 1.65-59 (m, 2H), δ1.53-1.48 (m, 2H), 1.01 (d, J=7.0 Hz, 3H), 0.88 (d, J=6.5 Hz, 3H), 0.67(d, J=7.0 Hz, 3H), 0.17 (d, J=7.0 Hz, 3H).

EXAMPLE 35 25-O-Desacetyl-(carbonyl-[1,4′]bipiperidinyl) 3-morpholinorifamycin S

Synthesis: The title compound was prepared as described above, using[1,4′]Bipiperidinyl in place of 1-methyl-piperazine. ESI MS m/z (M+H)⁺933, (M+H—OCH₃)⁺ 901; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s, 1H), 7.52 (s,1H), 6.98 (s, 0.5H), 6.39 (d, J=10.9 Hz, 1H), 6.2 (dd, J=5.9 and 16.4Hz, 1H), 6.04 (d, J=12.1 Hz, 1H), 5.05 (d, J=11 Hz, 1H), 4.93 (d, J=10.7Hz, 1H), 4.27-4.19 (m, 1H), 4.15-4.07 (m, 1H), 3.96-3.83 (m, 3H),3.77-3.68 (m, 2H), 3.61-3.52 (m, 2H), 3.50-3.47 (m, 1H), 3.36-3.28 (m,2H), 3.11 (s, 1.5H), 3.08 (s, 1.5H), 2.84-2.68 (m, 4H), 2.59-2.49 (m,4H), 2.27 (s, 3H), 2.26 (s, 3H), 2.18 (s, 3H), 1.96-1.76 (m, 7H), 1.74(s, 3H), 1.04 (d, J=7 Hz, 3H), 1.04 (d, J=6.6 Hz, 3H), 0.70 (d, J=6.6Hz, 3H), 0.21 (d, J=7 Hz, 3H).

EXAMPLE 3625-O-Desacetyl-(carbonyl-(4-aminomethyl-phenyl)-dimethyl-amine)3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using (4-aminomethyl-phenyl)-dimethyl-amine in place of1-methyl-piperazine. ESI MS m/z (M+H)⁺ 915, (M+H—OCH₃)⁺ 883; ¹H NMR (400MHz, CDCl₃) δ 13.25 (s, 1H), 7.51 (s, 1H), 7.11 (d, J=8.6 Hz, 2H), 6.66(d, J=8.6 Hz, 2H), 6.39 (d, J=11.0 Hz, 1H), 6.22 (dd, J=6.6 and 16.0 Hz,1H), 6.03 (d, J=12.5 Hz, 1H), 5.04 (dd, J=4.3 and 12.1 Hz, 1H), 4.96 (d,J=5.5 Hz, 1H), 4.85 (d, J=3.9 Hz, 1H), 4.22 (d, J=5.9 Hz, 2H), 3.97 (d,J=9.0 Hz, 1H), 3.92-3.87 (m, 3H), 3.76-3.68 (m, 3H), 3.56-3.51 (m, 3H),3.34-3.28 (m, 2H), 3.20-3.15 (m, 1H), 3.08 (s, 3H), 2.92 (s, 6H),2.37-2.32 (m, 1H), 2.26 (s, 3H), 2.12 (s, 3H), 1.90-1.76 (m, 2H), 1.74(s, 3H), 1.70-1.56 (m, 3H), 1.05 (d, J=7.0 Hz, 3H), 0.89 (d, J=7.0 Hz,3H), 0.66 (d, J=6.6 Hz, 3H), 0.17 (d, J=7.0 Hz, 3H).

EXAMPLE 3725-O-Desacetyl-(carbonyl-N′-benzyl-N,N-dimethyl-ethane-1,2-diamino)3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using N′-benzyl-N,N-dimethyl-ethane-1,2-diamine in place of1-methyl-piperazine. ESI MS m/z (M+H)⁺ 943, (M+H—OCH₃)⁺ 911; ¹H NMR (400MHz, CDCl₃) δ 13.25 (s, 1H), δ 7.48-7.44 (m, 1H), δ 7.26-7.15 (m, 4H), δ7.08 (d, J=7.0 Hz, 1H), δ 6.33 (d, J=10.2 Hz, 1H), δ 6.14 (dd, J=7.0 and16.0 Hz, 1H), δ 5.99 (d, J=12.1 Hz, 0.5H), δ 5.86 (d, J=12.1 Hz, 0.5H),δ 5.03-4.98 (m, 1H), δ 4.77 (dd, J=4.3 and 10.6 Hz, 1H), δ 4.43-4.35 (m,1H), δ 3.92-3.77 (m, 2H), δ 3.71-3.63 (m, 2H), δ 3.51-3.42 (m, 3H), δ3.28-3.17 (m, 3H), δ 3.10-3.08 (m, 1H), δ 3.03 (s, 1.5H), δ 2.99 (s,1.5H), δ 2.98-2.95 (m, 1H), δ 2.48-2.32 (m, 1H), δ 2.31-2.24 (m, 1H), δ3.51-3.42 (m, 3H), δ 2.20 (s, 1.5H), δ 2.19 (s, 1.5H), δ 2.18 (s, 1.5H),δ 2.13 (s, 1.5H), δ 1.89-1.70 (m, 4H), δ 1.68 (s, 1.5H), δ 1.67 (s,1.5H), δ 1.56-1.52 (m, 2H), ), δ 1.01-0.98 (m, 3H), δ 0.84-0.81 (m, 3H),δ 0.66 (d, J=6.6 Hz, 1.5H), δ 0.50 (d, J=6.6 Hz, 1.5H), δ 0.17 (d, J=7.0Hz, 1.5H), δ 0.07 (d, J=7.4 Hz, 1.5H),

EXAMPLE 38 25-O-Desacetyl-(carbonyl-2-(4-Chloro-phenyl)-ethylamine)3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using 2-(4-chloro-phenyl)-ethylamine in place of1-methyl-piperazine. ESI MS m/z (M+H)⁺ 920, (M+H—OCH₃)⁺ 888; ¹H NMR (400MHz, CDCl₃) δ 13.25 (s, 1H), 7.52 (s, 1H), 7.30-7.24 (m), 7.09 (d, J=7.0Hz, 2H), 6.38 (d, J=11.3 Hz, 1H), 6.20 (dd, J=5.5 and 15.6 Hz, 1H), 6.03(d, J=12.1 Hz, 1H), 5.03 (d, J=12.1 Hz, 1H), 4.91 (d, J=10.2 Hz, 1H),4.80-4.78 (m, 1H), 4.76-4.72 (m, 1H), 3.96-3.87 (m, 3H), 3.82-3.71 (m,3H), 3.55-3.29 (m, 6H), 3.06 (s, 3H), 2.78-2.72 (m, 2H), 2.39-2.30 (m,1H), 2.25 (s, 3H), 2.14 (s, 3H), 1.98-1.90 (m, 1H), 1.83-1.79 (m, 3H),1.74 (s, 3H), 1.62-1.53 (m, 2H), 1.04 (d, J=6.6 Hz, 3H), 0.90 (d, J=6.2Hz, 3H), 0.65 (d, J=6.6 Hz, 3H), 0.17 (d, J=7.0 Hz, 3H).

EXAMPLE 39 25-O-Desacetyl-(carbonyl-3-chloro-benzylamine) 3-morpholinorifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using 3-chloro-benzylamine in place of 1-methyl-piperazine. ESIMS m/z (M+H)⁺ 906, (M+H—OCH₃)⁺ 874; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s,1H), 7.55 (s, 1H), 7.25-7.29 (m, 5H), 7.14-7.11 (m, 1H), δ 6.39 (d,J=10.9 Hz, 1H), 6.20 (dd, J=6.6 and 16.0 Hz, 1H), 6.04 (d, J=13.7 Hz,1H), δ 5.18 (t, J=6.3 Hz, 1H), 5.05 (dd, J=4.7 and 12.5 Hz, 1H), 4.98(d, J=9.8 Hz, 1H), δ 6.67-6.64 (m, 1H), 4.31 (dd, J=6.3 and 11.7 Hz,2H), 3.95 (d, J=9.0 Hz, 1H), δ 3.92-3.87 (m, 3H), 3.79-3.71 (m, 3H),3.57-3.52 (m, 2H), 3.34-3.29 (m, 2H), 3.19-3.14 (m, 1H), 3.06 (s, 3H),2.38-2.32 (m, 1H), 2.26 (s, 3H), 2.12 (s, 3H), 1.87-1.79 (m, 2H), 1.74(s, 3H), 1.68-1.59 (m, 3H), δ 1.04 (d, J=6.6 Hz, 3H), 0.98 (d, J=7.0 Hz,3H), 0.69 (d, J=7.0 Hz, 3H), 0.19 (d, J=6.6 Hz, 3H).

EXAMPLE 40 25-O-Desacetyl-(carbonyl-4-nitro-benzylamine) 3-morpholinorifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using 4-nitro-benzylamine in place of 1-methyl-piperazine. ESI MSm/z (M+H)⁺ 916, (M+H—OCH₃)⁺ 884; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s,1H), 8.18 (d, J=8.6 Hz, 2H), 7.54 (s, 1H), 7.42 (d, J=8.6 Hz, 2H),7.21-7.14 (m, 1H), 6.37 (d, J=10.6 Hz, 1H), 6.17 (dd, J=6.3 and 16.0 Hz,1H), 6.04 (d, J=12.5 Hz, 1H), 5.35-5.32 (m, 1H), 5.05 (dd, J=5.1 and12.1 Hz, 1H), 4.96 (d, J=9.8 Hz, 1H), 4.54-4.50 (m, 1H), δ 4.46-4.32 (m,1H), 3.95-3.87 (m, 3H), 3.76-3.71 (m, 2H), δ 3.57-3.50 (m, 3H),3.34-3.29 (m, 2H), 3.15-3.11 (m, 1H), δ 3.05 (s, 3H), 2.39-2.31 (m, 1H),2.25 (s, 3H), 2.12 (s, 3H), 3.76-3.71 (m, 2H), 1.98-1.94 (m, 1H),1.87-1.79 (m, 2H), 1.74 (s, 3H), δ 1.69-1.57 (m, 4H), 3.76-3.71 (m, 2H),1.04 (d, J=7.0 Hz, 3H), 0.88 (d, J=7.0 Hz, 3H), 0.69 (d, J=7.0 Hz, 3H),0.19 (d, J=7.0 Hz, 3H).

EXAMPLE 41 25-O-Desacetyl-(carbonyl-N-quinolin-3-yl-methylamino)3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 6above, using C-Quinolin-3-yl-methylamine in place of1-methyl-piperazine. ESI MS m/z (M+H)⁺ 923, (M+H—OCH₃)⁺ 891; ¹H NMR (400MHz, CDCl₃) δ 13.25 (s, 1H), 8.23 (m, 1H), 8.10-8.07 (m, 2H), 7.77 (d,J=7.8 Hz, 1H), 7.73-7.70 (m, 1H), 7.58-7.52 (m, 2H), 7.25-7.18 (m, 1H),6.38 (d, J=11.3 Hz, 1H), 6.18 (d, J=6.3 and 15.6 Hz, 1H), 6.02 (d,J=12.1 Hz, 1H), 5.36-5.33 (m, 1H), 5.06-4.98 (m, 2H), 4.68-4.63 (m, 1H),4.54 (dd, J=6.3 and 12.5 Hz, 2H), 3.96-3.87 (m, 3H), 3.46-3.71 (m, 3H),3.53 (m, 2H), 3.39-3.28 (m, 2H), δ 3.17-3.11 (m, 1H), 3.00 (s, 3H),2.37-2.31 (m, 1H), 2.25 (s, 3H), 2.12 (s, 3H), 2.00-1.92 (m, 1H),1.88-1.78 (m, 2H), 1.73 (s, 3H), 1.69-1.58 (m, 4H), 1.00 (d, J=6.6 Hz,3H), 0.88 (d, J=6.6 Hz, 3H), 0.68 (d, J=6.6 Hz, 3H), 0.18 (d, J=7.0 Hz,3H).

EXAMPLE 4225-O-Desacetyl-(carbonyl-1-Cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S

Synthesis: The compound of Example 4 (10 mg, 0.010 mmol) was dissolvedin methylene chloride (1 ml). To this was added1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid (10 mg, 0.030 mmol) and N-methylmorpholine (6 μl, 0.050 mmol). Theresulting solution was stirred at room temperature for 30 minutes. Thereaction mixture was diluted with ethyl acetate (3 ml) and washed with 1M aqueous citric acid (3 ml) followed by washing with saturated sodiumchloride (3 ml). The resulting solution was dried with sodium sulfate,filtered, and evaporated to produce a dark solid. This residue was takenup in 1:2 (V/V) 1 M aqueous HCl/tetrahydrofuran (1 ml) and stirred for 3hours. After which time the mixture was diluted with ethyl acetate (3ml) and the aqueous layer was removed. This solution was vigorouslywashed with an aqueous solution consisting of 5% (W/V) potassiumferricyanide and 5% (W/V) sodium bicarbonate, which was then followed bymultiple washes with saturated sodium chloride. The resulting solutionwas dried with sodium sulfate, filtered, and evaporated. The residue waspurified by silica gel column chromatography (step gradient; (99.9%EtOAc/0.01% HOAc) to (89.9% EtOAc/10% MeOH/0.01% HOAc) to (49.9%EtOAc/50% MeOH/0.01% HOAc) to produce the title compound. ESI MS m/z(M+H)⁺ 1096; ¹H NMR (400 MHz, CDCl₃) δ 13.25 (s, 1H), 8.79 (s, 1H), 8.06(d, J=12.5 Hz, 1H), 7.56 (s, 1H), 6.36 (d, J=10.6 Hz, 1H), δ 6.16 (dd,J=6.6 and 16.4 Hz, 1H), 6.07 (d, J=10.9 Hz, 1H), 5.09 (dd, J=5.1 and13.7 Hz, 1H), 5.02 (d, J=10.2 Hz, 1H), δ 3.95-3.87 (m, 3H), 3.77-3.62(m, 4H), 3.58-3.50 (m, 3H), 3.35-3.22 (m, 5H), 3.12 (s, 3H), 2.38-2.33(m, 1H), 2.27 (s, 3H), 2.14-2.12 (m, 2H), 2.09 (s, 3H), 1.88-1.79 (m,1H), 1.74 (s, 3H), 1.05 (d, J=7.0 Hz, 3H), 0.89-0.78 (m, 7H), 0.72 (d,J=6.6 Hz, 3H), 0.24 (d, J=7.0 Hz, 3H).

EXAMPLE 43 25-O-Desacetyl-(carbonyl-prop-2-ynylamino) 3-morpholinorifamycin S

Synthesis: The title compound was prepared as described above usingprop-2-ynyl amine. ESI MS m/z (M+H)⁺ 820.0; ¹H NMR (400 MHz, CDCl₃) δ13.23 (s, 1H), 7.48 (s, 1H), 6.96 (s, 1H), 6.37 (d, J=11.0 Hz, 1H), 6.19(dd, J=15.7, 6.3 Hz, 1H), 6.03 (d, J=11.7 Hz, 1H), 6.37 (d, J=11.0 Hz,1H), 6.19 (dd, J=15.7, 6.3 Hz, 1H), 5.03 (d, J=11.7 Hz, 2H), 4.60-4.50(m, 1H), 3.98-3.84 (m, 4H), 3.78-3.68 (m, 3H), 3.56-3.48 (m, 2H), 3.15(br d, J=9.4 Hz, 1H), 3.11 (s, 3H), 2.34-2.28 (m, 1H), 2.24 (s, 3H),2.21 (app t, J=2.3 Hz, 1H), 2.10 (s, 3H), 2.03 (s, 2H), 1.90-1.72 (m,2H), 1.72 (s, 3H), 1.68-1.58 (m, 3H), 1.02 (d, J=7.0 Hz, 3H), 0.88 (d,J=7.0 Hz, 3H), 0.67 (d, J=7.0 Hz, 3H), 0.16 (d, J=7.0 Hz, 3H).

EXAMPLE 4425-O-Desacetyl-(carbonyl-[3-(3-amino-prop-1-ynyl)-phenyl]-methanol)3-morpholino rifamycin S

Synthesis: 3-Iodobenzyl alcohol (37 μL, 0.29 mmol), potassium carbonate(39 mg, 0.29 mmol), copper iodide (6.5 mg, 0.03 mmol), 10% Pd—C (1.1 mg,0.01 mmol), and triphenyl phosphine (9 mg, 0.03 mmol) was suspended in a1:1 mixture of 1,2-dimethoxyethane and water (0.8 mL). The suspensionwas stirred at room temperature for 30 minutes. The compound of Example43 (89 mg, 0.11 mmol) was then added in a 1:1 mixture of1,2-dimethoxyethane and water (0.8 mL) and the reaction mixture wasallowed to reflux overnight. After refluxing overnight, it was observedthat the palladium catalyst had plated out on the sides of the roundbottom flask. The reaction was cooled to room temperature, diluted withethyl acetate (25 mL) and washed sequentially with water and a saturatedpotassium ferricyanide phosphate buffer (pH=7.4). The organic layer wasseparated, dried over sodium sulfate and concentrated to give a purpleresidue. The acetonide was removed as described in the procedure for thepreparation of the title compound. The material was determined to bepure by ₁H NMR and LC/MS and was taken directly to the next step withoutfurther purification. ESI MS m/z (M+H)⁺ 926.1; ₁H NMR (400 MHz, CDCl₃) δ13.23 (s, 1H, 7.49 (s, 1H), 7.36 (s, 1H), 7.30-7.26 (m, 3H), 6.38 (d,J=11 Hz, 1H, 6.19 (dd, J=16.5, 7.0 Hz, 1H), 6.02 (d, J=11.7 Hz, 1H,5.12-4.92 (m, 3H), 4.68-4.58 (m, 2H), 4.20-4.08 (m, 2H), 3.93(d, J=9.4Hz, 1H, 3.92-3.84 (m, 2H), 3.78-3.68 (m, 3H), 3.56-3.48 (m, 3H),3.32-3.24 (m, 2H), 3.20-3.26 (m, 1H), 3.11 (s, 3H), 2.36-2.28 (m, 1H),2.24 (s, 3H), 2.10 (s, 2H), 1.90-1.76 (m, 2H), 1.72 (s, 3H), 1.64-1.56(m, 1H), 1.57 (s, 2H), 1.01 (d, J=7.0 Hz, 3H), 1.00-0.97 (m, 1H), 0.87(d, J=7.0 Hz, 3H), 0.88-0.86 (m, 1H, 0.76 (d, J=6.3 Hz, 1H, 0.68 (d,J=6.3 Hz, 2H), 0. 17 (d, J=7.0 Hz, 3H).

EXAMPLE 45 25-O-Desacetyl-(carbonyl-3-quinolin-3-yl-prop-2-ynylamine)3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 41above, using 3-bromoquinoline and the compound of Example 44. ESI MS m/z(M+H)⁺ 947.1; ₁H NMR (400MHz, CDCl₃) δ 13.23 (s, 1H), 8.82 (d, J=2.3 Hz,1H) 8.16 (d, J=1.6 Hz, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.78-7.68 (m, 2H),7.56 (app t, J=7.4 Hz, 1H), 7.49 (s, 1H), 7.22 (dd, J=11.7, 4.7 Hz, 1H),6.37 (d, J=11.0 Hz, 1H), 6.18 (dd, J=16.4, 6.3 Hz, 1H), 6.02 (d, J=11.7Hz, 1H), 5.18 (app t, J=5.5 Hz, 1H), 5.07 (dd, J=12.5, 4.7 Hz, 1H), 5.01(d, J=10.2 Hz, 1H), 4.59 (d, J=3.9 Hz, 1H), 4.23 (dd, J=12.5, 6.3 Hz,2H), 3.94 (d, J=9.4 Hz, 1H), 3.94-3.88 (m, 3H), 3.82-3.66 (m, 4H),3.56-3.46 (m, 2H), 3.19 (br d, J=10.2 Hz, 1H), 3.13 (s, 3H), 2.36-2.28(m, 1H), 2.24 (s, 2H), 2.10 (s, 3H), 1.90-1.77 (m, 2H), 1.71 (s, 3H),1.67-1.60 (m, 1H), 1.58 (s, 3H),1.02 (d, J=7.0 Hz, 3H), 0.87 (d, J=7.0Hz, 3H), 0.78 (app t, J=5.5 Hz, 1H), 0.69 (d, J=7.0 Hz, 3H), 0.17 (d,J=7.0 Hz, 3H).

EXAMPLE 4625-O-Desacetyl-(carbonyl-C-[3-(2-methoxy-phenyl)-isoxazol-5-yl]-methylamino)3-morpholino rifamycin S

Synthesis: 2-Methoxy-phenyl hydroximoyl chloride (Zamponi, et al., 2003)(7.5 mg, 0.04 mmol) was dissolved in anhydrous benzene (0.1 mL) at roomtemperature. To this solution was added triethylamine (5.5 μL, 0.04mmol). Formation of a white precipitate was observed. The compound ofexample 43 (31 mg, 0.04 mmol) in anhydrous benzene (0.6 mL) was thenadded dropwise. As judged by LC/MS, the reaction was 50% complete in onehour. The reaction was diluted with ethyl acetate (10 mL), washedsequentially with water and saturated potassium ferricyanide in aphosphate buffer (pH=7.4). The organic layer was dried over sodiumsulfate and concentrated to a purple residue. The residue was purifiedon preparative thin layer chromatography plates (50% ethylacetate/hexanes ) to give 10.7 mg of the title compound in 64% yield.ESI MS m/z (M+H—OCH₃ )⁺ 937.3; ₁H NMR (400 MHz, CDCl₃) δ 13.23 (s, 1H),7.86-7.77 (m, 1H), 7.48 (s, 1H), 7.42-7.35 (m, 1H), 7.22 (dd, J=15.6,11.0 Hz, 1H), 7.04-6.94 (m, 2H), 6.66 (s, 1H), 6.36 (d, J=11.0 Hz, 1H),6.17 (dd, J=15.7, 6.3 Hz, 1H), 6.03-5.93 (m, 1H), 5.36 (app t, J=6.3 Hz,1H), 5.03 (dd, J=12.5, 4.7 Hz, 1H), 4.98 (d, J=10.2 Hz, 1H, 4.59-4.40(m, 3H), 3.96-3.78 (m, 4H), 3.85 (s, 3H), 3.78-3.68 (m, 3H), 3.54-3.46(m, 3H), 3.32-3.24 (m, 2H), 3.16-3.08 (m, 1H), 3.03 (s, 3H), 2.36-2.26(m, 1H), 2.23 (s, 3H), 2.09 (s, 3H), 1.88-1.76 (m, 2H), 1.70 (s, 3H),1.68-1.54 (m, 2H), 0.98 (d, J=7.0 Hz, 3H), 0.86 (d, J=7.0 Hz, 3H), 0.67(d, J=6.3 Hz, 3H), 0.16 (d, J=7.0 Hz, 3H).

EXAMPLE 4725-O-Desacetyl-(carbonyl-C-(3-Pyridin-2-yl-isoxazol-5-yl)-methylamino)3-morpholino rifamycin S

Synthesis: 3-Pyridinyl hydroximoyl chloride (Kocevar, et al., 1988) (4.4mg, 0.03 mmol) was dissolved in anhydrous tetrahydrofuran (0.1 mL) atroom temperature. To this solution was added triethylamine (4 μL, 0.03mmol). The compound of Example 43 (21.4 mg, 0.03 mmol) in anhydroustetrahydrofuran (0.6 mL) was then added dropwise. After one hour,additional 3-pyridinyl hydroximoyl chloride (5 mg) and triethylamine (5μL) were added to the reaction and the mixture was stirred at roomtemperature overnight. The reaction mixture was diluted with ethylacetate (10 mL) and washed sequentially with water then saturatedpotassium ferricyanide phosphate buffer (pH=7.4). The organic layer wasdried over sodium sulfate and the purple residue purified on preparativethin layer chromatography plates (30% acetonitrile/chloroform) to givethe title compound, 8.5 mg (66% yield). ESI MS m/z (M+H)⁺ 940.1; ₁H NMR(400 MHz, CDCl₃) δ 13.07 (s, 1H), 8.48 (d, J=4.7 Hz, 1H), 7.83 (d, J=7.8Hz, 1H), 7.63 (dt, J=7.8, 1.6 Hz, 1H), 7.34 (s, 1H), 7.19-7.14 (m, 1H),7.06 (dd, J=16.4, 11.0 Hz, 1H), 6.64 (s, 1H), 6.21 (d, J=10.2 Hz, 1H),6.01 (dd, J=16.4, 6.3 Hz, 1H), 5.86 (dd, J=11.7, 1.6 Hz, 1H), 5.26 (appt, J=6.3 Hz, 1H), 4.88 (dd, J=12.5, 4.7 Hz, 1H), 4.84 (d, J=10.2 Hz,1H), 4.40-4.33 (m, 2H), 3.78 (d, J=10.2 Hz, 1H), 3.74-3.68 (m, 2H),3.60-3.49 (m, 2H), 3.40-3.32 (m, 2H), 3.19-3.10 (m, 2H), 2.99 (br d,J=10.2 Hz, 1H), 2.90 (s, 3H), 2.20-2.12 (m, 1H), 2.07 (s, 3H), 1.94 (s,3H), 1.72-1.60 (m, 3H), 1.55 (s, 3H), 1.48-1.40 (m, 2H), 0.84 (d, J=7.0Hz, 3H), 0.71 (d, J=7.0 Hz, 3H), 0.52 (d, J=7.0 Hz, 3H), 0.01 (d, J=7.0Hz, 3H).

EXAMPLE 48 25-O-Desacetyl-(carbonyl-(3-acetyl-isoxazol-5-ylmethylamino)3-morpholino rifamycin S

Acetyl hydroximoyl chloride (Kim, Jung, 1981) (5 mg, 0.04 mmol) wasdissolved in anhydrous ethyl acetate (0.1 mL) at room temperature. Tothis solution was added sodium bicarbonate (17 mg, 0.20 mmol). Thecompound of Example 43 (31 mg, 0.04 mmol) in anhydrous ethyl acetate(0.6 mL) was then added dropwise. After one hour, additional acetylhydroximoyl chloride (5 mg) and sodium bicarbonate (17 mg) was added tothe reaction and the mixture allowed to stir at room temperatureovernight. Upon consumption of starting material, the reaction wasdiluted with ethyl acetate (10 mL) and washed sequentially with waterand a saturated potassium ferricyanide phosphate buffer (pH=7.4). Theorganic layer was dried over sodium sulfate and concentrated to a purpleresidue. Residue was purified on preparative thin layer chromatographyplates (50% ethyl acetate/hexanes) to give the title compound, 10.9 mg(68% yield) as a 3:7 mixture of regioisomers. ESI MS m/z (M+H)⁺ 905.1;₁H NMR (400 MHz, CDCl₃) δ 13.07 (s, 1H, 7.34 (s, 1H), 7.01 (dd, J=15.7,11.0 Hz, 1H), 6.35 (s, 1H), 6.20 (d, J=10.2 Hz, 1H), 6.00 (dd, J=15.7,6.3 Hz, 1H), 5.87 (dd, J=12.5, 1.6 Hz, 1H), 5.19 (app t, J=6.3 Hz, 1H),4.86 (dd, J=12.5, 5.5 Hz, 2H), 4.81 (d, J=10.2 Hz, 1H), 4.34 (dd,J=11.7, 6.3 Hz, 1H), 4.23 (d, J=3.9 Hz, 1H), 3.80-3.68 (m, 3H),3.60-3.52 (m, 2H), 3.49 (s, 1H), 3.40-3.28 (m, 3H), 3.17-3.10 (m, 2H),2.98-2.92 (m, 1H), 2.88 (s, 3H), 2.44 (s, 3H), 2.08 (s, 3H), 1.94 (s,3H), 1.70-1.60 (m, 1H), 1.56 (s, 3H), 1.52-1.40 (m, 2H), 1.25 (s, 2H),0.86 (d, J=7.0 Hz, 3H), 0.71 (d, J=7.0 Hz, 3H), 0.52 (d, J=7.0 Hz, 3H),0.01 (d, J=7.0 Hz, 3H).

EXAMPLE 4925-O-Desacetyl-(carbonyl-N-hydroxy-N′-phenyl-4-(2-piperazin-1-yl-ethylamino)-3-trifluoromethyl-benzamidine)3-morpholino rifamycin S

Synthesis:N-Hydroxy-N′-phenyl-4-(2-piperazin-1-yl-ethylamino)-3-trifluoromethyl-benzamidinewas prepared as previous described (International Patent ApplicationPublication No. WO 200/051456 A2) and reacted with the compound ofExample 5, as described in Example 6, to give the title compound. ₁H NMR(400 MHz, CD₃OD) δ 7.45 (d, J=2.3 Hz, 1H), 7.34 (dd, J=8.6, 1.6 Hz, 1H),7.11 (t, J=7.8 Hz, 2H), 6.89 (t, J=7.8 Hz, 1H), 6.72 (t, J=7.8 Hz, 3H),5.60 (app t, J=4.7 Hz, 1H), 3.24 (t, J=4.7 Hz, 2H), 2.84 (t, J=4.7 Hz,4H), 2.63 (t, J=6.3 Hz, 2H), 2.47 (br s, 4H).

EXAMPLE 50N-(2-Methyl-1H-indol-5-yl)-4-piperazin-1-yl-3-trifluoromethyl-benzamide

Synthesis: 4-Fluoro-3-trifluoromethyl benzoyl chloride (0.42 mL, 2.77mmol) was added to a solution of 2-methyl-1H-indol-5-ylamine (472 mg,3.23 mmol) and triethylamine (0.42 mL, 3.01 mmol) in anhydrousdichloromethane at room temperature. The reaction mixture was stirred atroom temperature for two hours then diluted with a 1:1 mixture of ethylacetate and water (80 mL). The organic layer was washed sequentiallywith 0.5N HCl, saturated NaHCO₃, water, saturated NaCl and dried overanhydrous sodium sulfate. The desired4-fluoro-N-(2-methyl-1H-indol-5-yl)-3-trifluoromethyl-benzamide wasobtained as a purple solid in nearly quantitative yield. This materialwas taken onto the next step without further purification.4-Fluoro-N-(2-methyl-1H-indol-5-yl)-3-trifluoromethyl-benzamide (1.02 g,3.03 mmol) and piperazine (1.83 g, 21.21 mmol) was dissolved inN,N-dimethylformamide (10 mL). The reaction mixture was heated in asealed glass tube at 125° C. for two and a half hours. The crude mixturewas then cooled to room temperature, concentrated and the residuechromatographed with 10% MeOH/CH₂Cl₂+2% triethylamine to affordN-(2-Methyl-1H-indol-5-yl)-4-piperazin-1-yl-3-trifluoromethyl-benzamide,the title compound (86% yield). ¹H NMR (400 MHz , CD₃OD) δ 8.26 (d,J=2.3 Hz, 1H), 8.18 (dd, J=8.6, 2.3 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H, 7.55(d, J=8.6 Hz, 1H), 7.28-7.17 (m, 2H), 2.99 (s, 8H), 2.41 (s, 3H).

EXAMPLE 5125-O-Desacetyl-(carbonyl-N-(2-methyl-1H-indol-5-yl)-4-piperazin-1-yl-3-trifluoromethyl-benzamide)3-morpholinorifamycin S

Synthesis:N-(2-Methyl-1H-indol-5-yl)-4-piperazin-1-yl-3-trifluoromethyl-benzamidewas reacted with the compound of Example 5, as described in Example 6,to give the title compound. ESI MS m/z (M+H)⁺ 1167.1; ¹H NMR (400 MHz ,CDCl₃)δ 13.20 (s, 1H), 8.10 (s, 1H), 8.03-7.96 (m, 1H), 7.91 (s, 1H),7.75 (d, J=16.4 Hz, 1H), 7.48 (s, 1H), 7.35 (s, 1H), 6.91 (s, 1H), 6.73(dd, J=16.4, 11.0 Hz, 1H), 5.01 (dd, J=12.5, 4.7 Hz, 1H), 4.95 (s, 1H),3.94-3.80 (m, 3H), 3.74-3.64 (m, 3H), 3.56 (br s, 1H), 3.52-3.44 (m,3H), 3.32-3.22 (m, 3H), 3.09 (s, 3H), 2.86 (s, 4H), 2.38 (s, 3H),2.35-2.22 (m, 1H), 2.20 (s, 3H), 2.05 (s, 3H), 1.68 (s, 3H), 1.62-1.59(m, 1H), 1.36 (s, 8H), 1.01 (d, J=7.0 Hz, 3H), 0.90-0.72 (m, 8H), 0.66(d, J=7.0 Hz, 3H), 0.17 (d, J=7.0 Hz, 3H).

EXAMPLE 52N-(5-Methoxy-pyridin-3-yl)-4-piperazin-1-yl-3-trifluoromethyl-benzamide

Synthesis: The title compound was prepared as described in Example 50,using 3-amino-5-methoxypyridine in place of 2-methyl-1H-indol-5-ylamine.¹H NMR (400 MHz, CD₃OD) δ 8.43 (d, J=2.3 Hz, 1H), 8.27 (d, J=1.6 Hz,1H), 8.18 (dd, J=8.6, 3.1 Hz, 1H), 8.01 (dd, J=9.4, 3.1 Hz, 1H), 7.56(d, J=8.6 Hz, 1H), 6.83 (d, J=9.4 Hz, 1H), 3.91 (s, 3H), 3.02 (s, 8H).

EXAMPLE 5325-O-Desacetyl-(carbonyl-N-(5-methoxy-pyridin-3-yl)-4-piperazin-1-yl-3-trifluoromethyl-benzamide)3-morpholinorifamycin S

Synthesis: The compound of Example 5 was treated withN-(5-methoxy-pyridin-3-yl)-4-piperazin-1-yl-3-trifluoromethyl-benzamide,as described in Example 6, to give compound the title compound. ESI MSm/z (M+H)⁺ 1145.1; ¹H NMR (400 MHz , CDCl₃) δ 13.20 (s, 1H), 8.22 (d,J=2.3 Hz, 1H), 8.10 (d, J=1.6 Hz, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.95 (dd,J=8.6, 2.3 Hz, 1H), 7.85 (s, 1H), 7.48 (s, 1H), 7.28 (d, J=8.6 Hz, 1H),6.91 (s, 1H), 6.72 (d, J=9.4 Hz, 1H), 5.01 (dd, J=11.7, 4.7 Hz, 1H),4.96-4.94 (m, 2H), 4.80 (br s, 1H), 3.87 (s, 3H), 3.84-3.80 (m, 2H),3.72-3.64 (m, 3H), 3.57 (br s, 4H), 3.52-3.43 (m, 3H), 3.08 (s, 3H),2.86 (br s, 5H), 2.32-2.26 (m, 1H), 2.20 (s, 3H), 2.05 (s, 2H),1.92-1.72 (m, 3H), 1.68 (s, 2H), 1.65-1.60 (m, 2H), 1.36 (s, 6H), 1.00(d, J=7.0 Hz, 3H), 0.83 (d, J=7.0 Hz, 3H), 0.66 (d, J=7.0 Hz, 3H), 0.17(d, J=7.0 Hz, 3H).

EXAMPLE 54 25-O-Desacetyl-(carbonyl-N-(4-piperidone))cyclic-21,23-(1-methylethylidene acetal) 3-morpholino rifamycin S

Synthesis: The compound of Example 5 was treated with 4-piperidonehydrochloride and N-methylmorpholine, as described in Example 6, to givecompound the title compound. ESI MS m/z (M+H)⁺ 904.0.

EXAMPLE 5525-O-Desacetyl-(carbonyl-N-(1-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S

Synthesis: The compound of Example 54 (100 mg, 0.11 mmol) was treatedwith1-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid (53 mg, 0.12 mmol) and NaBH(OAc)₄ (70 mg, 0.33 mmol) and stirred at23° C. for 6 hr the mixture is diluted with ethyl acetate and washedwith water. The ethyl acetate layer is washed with a dilute K₃Fe(CN)₆ inpH 7.4 phosphate buffer. The residue is purified by preparative TLC andthe product dissolved in THF and treated with 1 N HCl (aq) to remove theacetonide and give compound the title compound. ESI MS m/z (M+H)⁺1249.38.

EXAMPLE 5625-O-Desacetyl-(carbonyl-N-(7-(3-amino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S

Synthesis: The compound of Example 56 was prepared as described forExample 55 using7-(3-amino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid; ESI MS m/z (M+H)⁺ 1209.3.

EXAMPLE 5725-O-Desacetyl-(carbonyl-N-(1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S

Synthesis: The compound of Example 57 was prepared as described forExample 55 using1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid; ESI MS m/z (M+H)⁺ 1179.3.

EXAMPLE 5825-O-Desacetyl-(carbonyl-N-(7-(4-amino-piperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S

Synthesis: The compound of Example 58 was prepared as described forExample 55 using7-(4-amino-piperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid; ESI MS m/z (M+H)⁺ 1223.3.

EXAMPLE 5925-O-Desacetyl-(carbonyl-N-(7-(3-amino-piperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S

Synthesis: The compound of Example 59 was prepared as described forExample 55 using7-(3-amino-piperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid; ESI MS m/z (M+H)⁺ 1223.3.

EXAMPLE 6025-O-Desacetyl-(carbonyl-N-(1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S

Synthesis: The compound of Example 60 was prepared as described forExample 55 using1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid; ESI MS m/z (M+H)⁺ 1209.3.

EXAMPLE 61 25-O-Desacetyl-(carbonyl-N-(3-pyrrolidone)cyclic-21,23-(1-methylethylidene acetal)-3-morpholino rifamycin S

Synthesis: The compound of Example 5 was treated with 3-pyrrolidinonehydrochloride and N-methylmorpholine, as described in Example 6, to givecompound the title compound. ESI MS m/z (M+H)⁺ 889.9.

EXAMPLE 6225-O-Desacetyl-(carbonyl-N-(1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-(4-pyrrolidin-3-yl-piperazin-1-yl)-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S

Synthesis: The compound of Example 62 was prepared as described forExample 55 using1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid; ESI MS m/z (M+H)⁺ 1195.3.

EXAMPLE 6325-O-Desacetyl-(carbonyl-N-(7-[3-(2-amino-acetylamino)-pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid 3-morpholino rifamycin S

Synthesis: The compound of Example 5 (125 mg, 0.13 mmol) was dissolvedin methylene chloride (3 ml) and treated withtert-Butoxycarbonylamino-acetic acid ethyl ester (75 mg, 0.39 mmol) andN-methylmorpholine (42 ul, 0.39 mmol). The resulting solution wasstirred at room temperature for 30 minutes. The reaction mixture wasdiluted with ethyl acetate (10 ml) and washed with 1 M aqueous citricacid (10 ml) followed by washing with saturated sodium chloride (10 ml).The resulting solution was dried with sodium sulfate, filtered, andevaporated to produce a dark solid. This residue was taken up in 1:4(V/V) 1 M NaOH/tetrahydrofuran (5 ml) and stirred for 3 hours. Afterwhich the mixture was neutralized with 1 M citric acid and diluted withethyl acetate and the aqueous layer was removed. The resulting solutionwas dried with sodium sulfate, filtered, and evaporated to produce adark solid. This residue was taken up in DMF (3.0 ml) and to thissolution was added EDCl (42 mg, 0.22 mmol), N-O-hydroxysuccinimide (25mg, 0.22 mmol), and dimethylaminopyridine (3 mg, 0.022 mmol). Theresulting solution was stirred for 3.5 hours. At which time water (10ml) was added. The resulting precipitate was filted and washed withwater. The collected solid was dissolved in methylene chloride, driedwith MgSO₄, and evaporated to yield a dark solid. This residue was takenup in methylene chloride (3 ml). To this solution was added7-(3-amino-pyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid (70 mg). The resulting solution was stirred for 2 hours. Afterwhich the solution was washed with water (2×2ml), dried with MgSO₄, andevaporated to a dark solid. This residue was taken up in 1:2 (V/V) 1 Maqueous HCl/tetrahydrofuran (1 ml) and stirred for 3 hours. After whichtime the mixture was diluted with ethyl acetate (3 ml) and the aqueouslayer was removed. This solution was vigorously washed with an aqueoussolution consisting of 5% (W/V) potassium ferricyanide and 5% (W/V)sodium bicarbonate, which was then followed by multiple washes withsaturated sodium chloride. The resulting solution was dried with sodiumsulfate, filtered, and evaporated to produce the crude product. Thecrude mixture was purified on silica by preparatory TLC with 5%methanol/95% dichloromethane to produce the title compound, 9 mg. ESI MSm/z (M+H)⁺ 1187, (M+H—OCH₃)⁺ 1155.

EXAMPLE 6425-O-Desacetyl-(carbonyl-N-(7-[4-(2-amino-acetyl)-piperazin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid 3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 63above, using1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid in place of7-(3-amino-pyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid. ESI MS m/z (M+H)⁺ 1182, (M+H—OCH₃)⁺ 1150.

EXAMPLE 6525-O-Desacetyl-(carbonyl-N-(7-[4-(Azetidine-3-carbonyl)-3-methyl-piperazin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in Example 63above, using azetidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methylester in place of tert-butoxycarbonylamino-acetic acid methyl ester andusing1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid in place of7-(3-amino-pyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid. ESI MS m/z (M+Na)⁺ 1245, (M+H—OCH₃)⁺ 1191.

EXAMPLE 6625-O-Desacetyl-(carbonyl-N-(7-[4-(azetidine-3-carbonyl)-piperazin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid) 3-morpholino rifamycin S

Synthesis: The title compound was prepared as described in example 63above, using azetidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methylester in place of tert-butoxycarbonylamino-acetic acid methyl ester andusing1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid in place of7-(3-amino-pyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid. ESI MS m/z (M+H)⁺ 1209; (M+Na)⁺ 1231, (M+H—OCH₃)⁺ 1177.

EXAMPLE 6725-O-Desacetyl-(carbonyl-N-7-(3-amino-pyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S

Synthesis: The compound of Example 62 was prepared as described forExample 55 using7-(3-amino-pyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid; ESI MS m/z (M+H)⁺ 1130.2.

EXAMPLE 6825-O-Desacetyl-(carbonyl-N-(8-chloro-1-cyclopropyl-6-fluoro-7-(3-formylamino-pyrrolidin-1-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid)-3-morpholino-11-deoxy-11-hydroxyiminorifamycin S

Synthesis: To a stirred solution of example 67 (1 eq) in MeOH and THFwas added pyridine (13 eq) and hydroxylamine hydrochloride (13 eq). Thereaction solution was allowed to stir 5 days at room temperature. Thereaction mixture was purified by preparative thin layer chromatography(10% MeOH/DCM) to give the title compound as a purple-brown solid. ESIMS m/z 1145.63 (M+H)⁺.

EXAMPLE 6925-O-Desacetyl-(carbonyl-N-(2-dimethylamino-ethyl)-3-morpholino-11-deoxy-11-hydroxyiminorifamycinS

Synthesis: To a stirred solution of example 30 (1 eq) in MeOH and THFwas added pyridine (13 eq) and hydroxylamine hydrochloride (13 eq). Thereaction solution was allowed to stir 5 days at room temperature. Thereaction mixture was purified by preparative thin layer chromatography(10% MeOH/DCM) to give the title compound as a purple-brown solid. ESIMS m/z 867.9 (M+H)⁺.

References Cited

The content of each of the following documents is hereby incorporated byreference.

U.S. Patent Documents

-   U.S. Pat. No. 4,188,321-   U.S. Pat. No. 5,786,350

Other Patent Documents

-   International Patent Application Publication No. WO 01/051456 A2-   International Patent Application Publication No. WO 03/045319 A2

Other Publications

-   Brufani, M., Cerrini, S., Fedeli, W., Vaciago, A. J Mol. Biol. 1974,    vol. 87, pp. 409-35.-   Farr, B. M. Rifamycins, in Principles and Practice of Infectious    Diseases; Mandell, G. L., Bennett, J. E., Dolin, R., Eds.;    Churchhill Livingstone: Philadelphia, pp. 348-361.-   Greene, T. H. and Wuts, P. G. M., Protective Groups in Organic    Synthesis, 2nd edition, John Wiley & Sons, New York, 1991.-   Ince & Hooper, Antimicrobial Agents and Chemotherapy, 2000, vol. 44,    pp. 3344-50.-   Kim, Y. H., Jung, S. H., Tet. Lett., vol. 22(25), pp. 2371-2, 1981.-   Kocevar, M., et al., Syn. Comm., vol. 18(12), pp. 1427-32, 1988.-   Kump and Bickel, Helv. Chim. Acta., 1973, vol. 56(7), pp. 2323-47.-   National Committee for Clinical Laboratory Standards, 2000, Methods    for dilution antimicrobial susceptibility tests for bacteria that    grow aerobically, 5th ed. M7-A5, Wayne, Pa.-   Wehrli, Zimmerman, et al. Journal of Antibiotics, 1987, vol. 40(12),    pp. 1733-39.-   Zamponi, G. W., et al. J of Med. Chem., vol. 46(1), pp. 87-96, 2003.

1. A compound having a formula:

or its corresponding quinone form:

or its salts, hydrates, prodrugs or mixtures thereof; wherein, X ishydrogen, —NR₁₁R₁₂, —CH₂NR₁₁R₁₂, —C═NNR₁₁R₁₂, —SR₁₃, or -L₃-Q₃, whereinL₃ is any combination of 1 to 5 of the following structures:(C₁-C₆)alkylene, (C₁-C₆)alkenylene, (C₁-C₆)alkynylene,(C₃-C₈)cycloalkylene, heterocycle having from 1 to 3 heteroatoms,arylene, and heteroarylene, wherein L₃ optionally has any combination of1 to 3 heteroatoms selected from N, O and S, and wherein the carbon ornitrogen atoms of L₃ are optionally substituted by any combination of 1to 3 substituents selected from (C₁-C₆)alkyl, heterocycloalkyl, amino,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, hydroxyl, and (C₁-C₆)alkoxy,wherein R₁₁ and R₁₂ independently are hydrogen, (C₁-C₆)alkyl, orsubstituted (C₁-C₆)alkyl, or R₁₁ and R₁₂, together with the nitrogenatom to which they are attached, form a 4- to 8-membered heterocyclicring, optionally containing a second heteroatom selected from oxygen,nitrogen and sulfur, wherein one of the carbon or nitrogen atoms of theheterocyclic ring is optionally substituted by (C₁-C₆)alkyl orsubstituted (C₁-C₆)alkyl, and wherein R₁₃ is (C₁-C₆)alkyl or substituted(C₁-C₆)alkyl; Y is OR₁, when the compound is the Formula I, wherein R₁is hydrogen, (C₁-C₆)alkyl, substituted (C₁-C₆)alkyl, —CH₂COOH, or—CH₂CONR₁₁R₁₂, or Y is ═O, when the compound is the Formula II, or X andY, together with C-3 and C-4 of the Formula I or Formula II, jointogether to form a heterocyclic ring as shown in any of Formulas III,IV, V or VI:

wherein R₁₅ is —NR₂₀R₂₁, R₁₆ is hydrogen, OH or NH₂, R₁₇ is hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, (C₃-C₈)cycloalkyl, aryl,heteroaryl, or heterocycloalkyl, R₁₈ is (C₁-C₆)alkyl, (C₁-C₆)alkenyl,(C₁-C₆)alkynyl, (C₃-C₈)cycloalkyl, aryl, heteroaryl, —NR₂₀R₂₁, orheterocycloalkyl, R₁₉ is (C₁-C₆)alkyl or -NR₂₀R₂₁, R₂₀ and R₂₁,independently are alkyl, cycloalkyl, aryl, or heteroaryl, or R₂₀ andR₂₁, together with the nitrogen atom to which they are attached, form a4-8 membered heterocyclic ring containing one or two heteroatomsoptionally substituted with hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkenyl,(C₁-C₆)alkynyl, or (C₃-C8)cycloalkyl; Z is ═O, ═NH or ═NOR₁₄, whereinR₁₄ is —H, alkyl, aryl, heteroaryl or -L₁₁-Q₁₁, wherein L₁₁ is anycombination of 1 to 5 of the following structures: (C₁-C₆)alkylene,(C₁-C₆)alkenylene, (C₁-C₆)alkynylene, (C₃-C₈)cycloalkylene, heterocyclecontaining 1 to 3 heteroatoms, arylene, and heteroarylene, wherein L₁₁optionally has any combination of 1 to 3 heteroatoms selected from N, Oand S, and wherein the carbon or nitrogen atoms of L₁₁ are optionallysubstituted by any combination of 1 to 3 substituents selected from(C₁-C₆)alkyl, heterocycloalkyl, amino, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, hydroxyl, and (C₁-C₆)alkoxy; R₂ and R₃independently are hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkenyl,(C₁-C₆)alkynyl, aryl, heteroaryl or -L₂₅-Q₂₅, wherein L₂₅ is anycombination of 1 to 5 of the following structures: (C₁-C₆)alkylene,(C₁-C₆)alkenylene, (C₁-C₆)alkynylene, (C₃-C₈)cycloalkylene, heterocyclecontaining 1 to 3 heteroatoms, arylene, and heteroarylene, wherein L₂₅optionally has any combination of 1 to 3 heteroatoms selected from N, Oand S, and wherein the carbon or nitrogen atoms of L₂₅ are optionallysubstituted by any combination of 1 to 3 substituents selected from(C₁-C₆)alkyl, heterocycloalkyl, amino, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, hydroxyl, and (C₁-C₆)alkoxy, or R₂ and R₃, togetherwith the nitrogen atom to which they are attached, form a 4- to8-membered heterocyclic ring containing one or two heteroatoms, whereinthe carbon or nitrogen atoms of the ring are optionally substituted withone or more of hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, hydroxyl, and (C₁-C₆)alkoxy; and Q₃, Q₁₁, and Q₂₅are a pharmacophore, therapeutic drug, or antibacterial agentindependently comprising a quinolone, a macrolide, an oxazolidinone, anaminoglycoside, a tetracycline or any antibacterial pharnacophore. 2.The compound of claim 1, wherein L₃, L₁₁, and L₂₅ independently compriseany combination of from one to three of the following structures:


3. The compound of claim 1, wherein the pharmacophore or the therapeuticdrug or the antibacterial agent Q₃, Q₁₁, or Q₂₅ comprises a quinolone, amacrolide, or an oxazolidinone core.
 4. The compound of claim 1, whereinone or more of Q₃, Q₁₁, and Q₂₅ independently comprise one of thefollowing structures:

wherein, Ri is (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, substituted(C₃-C₆)cycloalkyl, aryl, substituted aryl, heteroaryl, or substitutedheteroaryl; Rii is hydrogen, halogen, amino, nitro or methyl; Riii andRiv independently are hydrogen or (C₁-C₆)alkyl, or Riii and Riv,together with the carbon atom to which they are attached, form a 3- to6-membered carbocycle; A₆ is C—H, C—F, or N; A₈ is C—H, C—F, C—Cl, C—Me,C—OMe, C—OCH₂F, C—OCHF₂, or N; and A₉ is CH₂, O or S.
 5. The compound ofclaim 3, wherein one or more of Q₃, Q₁₁, and Q₂₅ independently comprise:


6. The compound of claim 1, wherein one or more of Q₃, Q₁₁, and Q₂₅independently comprise one of the following structures:

wherein, Ra is hydrogen or hydroxyl; Xa is —O—, —NH—, or —CH₂NH—; Rb is-Xb-Rx, wherein Xb is absent or is L₂₅; Rx is (C₁-C₆)alkyl, substituted(C₁-C₆)alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, or a rifamycin moiety; Rc and Rd independently are hydrogen,hydroxyl, amino, alkylamino, dialkylamino, or —NH-Xb-Rx, wherein one ofRc and Rd is hydrogen and the other is hydroxyl, amino, alkylamino,dialkylamino, or —NH-Xb-Rx, or Rc and Rd, together with the carbon atomto which they are attached, form C═O or C═N—O-Xb-Rx; Re is (C₁-C₆)alkyl,substituted (C₁-C₆)alkyl, or -Xb-Rx; Rf is hydrogen, (C₁-C₆)alkyl, orsubstituted (C₁-C₆)alkyl; Rg is hydrogen, acetyl or propionyl; Rh ismethyl or methoxyl; Ri is —CH₂CHO, —CH₂CH═N—O-Xb-Rx, or—CH₂CH₂—NH-Xb-Rx; Rj is hydrogen or methyl; Rk is hydrogen or—CH₂—O-sugar; and Rl is methyl or ethyl.
 7. The compound of claim 6,wherein one or more of Q₃, Q₁₁, and Q₂₅ is covalently coupled to itscorresponding linker, L₃, L₁₁, or L₂₅, at its C-4″, C-6, C-9, or C-9aposition and is covalently coupled to the rifamycin moiety of theFormula I or the Formula II at its corresponding position C₃, C₁₁, orC₂₅.
 8. The compound of claim 6, wherein one or more of Q₃, Q₁₁, and Q₂₅independently comprise:


9. The compound of claim 1, wherein one or more of Q₃, Q₁₁, and Q₂₅independently comprise the following structure:

wherein, Ry and Rz independently are H or F; and Xg is L₃, L₁₁ or L₂₅.10. The compound of claim 1, wherein the compound is:25-O-desacetyl-(1-carbonyl-4-methyl-piperazine) 3-morpholino rifamycinS, 25-O-desacetyl-(1-carbonyl-isobutylamino) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-allylamino) 3-morpholino rifamycin S,25-O-desacetyl(1-carbonyl-2-(4-methyl-piperazin-1-yl)-ethylamine)3-morpholino rifamycin S, 25-O-desacetyl(1-carbonyl-2-diethylamine)3-morpholino rifamycin S,25-O-desacetyl-(1-carbonyl-3-imidazol-1-yl-propylamine) 3-morpholinorifamycin S, 25-O-desacetyl(1-carbonyl-1-(4-fluorophenyl)-piperazine)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-1-(3-trifluoromethylbenzylamino)) 3-morpholinorifamycin S, 25-O-desacetyl-(carbonyl-1-pyrrolidino) 3-morpholinorifamycin S, 25-O-desacetyl (carbonyl-benzyl) 3-morpholino rifamycin S,25-O-desacetyl-(4-carbonyl-1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(8-chloro-1-cyclopropyl-7-[4-(1-carbonyl)-piperazin-1-yl]-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(1-carbonyl-(2-pyridin-2-yl-ethylamine)) 3-morpholinorifamycin S, 25-O-desacetyl-(1-carbonyl-2-thiophen-2-yl-ethylamine)3-morpholino rifamycin S, 25-O-desacetyl-(1-carbonyl-2-aminoethanol)3-morpholino rifamycin S, 25-O-desacetyl-(carbonyl-methylamino)3-morpholino rifamycin S, 25-O-desacetyl-(carbonyl-4-chlorobenzyl)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-naphthalen-1-ylmethyl-amino) 3-morpholinorifamycin S, 25-O-desacetyl-(carbonyl-3-phenylpropylamino) 3-morpholinorifamycin S, 25-O-desacetyl-(carbonyl-3-phenylethylamino) 3-morpholinorifamycin S, 25-O-desacetyl-(carbonyl-4-methoxybenzylamino) 3-morpholinomorpholino rifamycin S, 25-O-desacetyl-((2-amino-ethyl)-carbamic acid6-[6-(4-dimethylamino-3-hydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-oxacyclotetradec-4-yloxy]-4-methoxy-2,4-dimethyl-tetrahydro-pyran-3-ylester) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-2-ethyl-octahydro-pyrrolo[3,4-c]pyrrole)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N,N-dimethylethylenediamine) 3-morpholinorifamycin S,25-0-desacetyl-(carbonyl-2-(1-methyl-pyrrolidin-2-yl)-ethylamine)3-morpholinorifamycin S, 25-O-desacetyl-(carbonyl-2-pyrrolidin-1-yl-ethylamine)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-1-benzyl-piperidin-4-ylamine) 3-morpholinorifamycin S, 25-O-desacetyl-(carbonyl-4-phenyl-butylamine) 3-morpholinorifamycin S, 25-O-desacetyl-(carbonyl-[1,4′]bipiperidinyl) 3-morpholinorifamycin S,25-O-desacetyl-(carbonyl-(4-aminomethyl-phenyl)-dimethyl-amine)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N′-benzyl-N,N-dimethyl-ethane-1,2-diamino)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-2-(4-chloro-phenyl)-ethylamine) 3-morpholinorifamycin S, 25-O-desacetyl-(carbonyl-3-chloro-benzylamine) 3-morpholinorifamycin S, 25-O-desacetyl-(carbonyl-4-nitro-benzylamine) 3-morpholinorifamycin S, 25-O-desacetyl-(carbonyl-N-(quinolin-3-yl-methylamino))3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-prop-2-ynylamino) 3-morpholino rifamycin S,25-O-deacetyl cyclic-21,23-(1-methylethylideneacetal)-(carbonyl-prop-2-ynylamino)-3-morpholino-rifamycin S,25-O-desacetyl-(carbonyl-[3-(3-amino-prop-1-ynyl)-phenyl]-methanol)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-3-quinolin-3-yl-prop-2-ynylamine) 3-morpholinorifamycin S,25-O-desacetyl-(carbonyl-C-[3-(2-methoxy-phenyl)-isoxazol-5-yl]-methylamino)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-C-(3-pyridin-2-yl-isoxazol-5-yl)-methylamino)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-(3-acetyl-isoxazol-5-ylmethylamino)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-hydroxy-N′-phenyl-4-(2-piperazin-1-yl-ethylamino)-3-trifluoromethyl-benzamidine)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(2-methyl-1H-indol-5-yl)-4-piperazin-1-yl-3-trifluoromethyl-benzamide)3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(5-methoxy-pyridin-3-yl)-4-piperazin-1-yl-3-trifluoromethyl-benzamide)3-morpholino rifamycin S, 25-O-desacetyl-(carbonyl-N-(4-piperidone)cyclic-21, 23-(1-methylethylidene acetal) 3-morpholino rifamycin S25-O-desacetyl-(carbonyl-N-(1-cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(7-(3-amino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(7-(4-amino-piperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(7-(3-amino-piperidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(3-pyrrolidone)cyclic-21,23-(1-methylethylidene acetal)-(3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-(4-pyrrolidin-3-yl-piperazin-1-yl)-1,4-dihydro-quinoline-3-carboxylicacid 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(7-[3-(2-amino-acetylamino)-pyrrolidin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(7-[4-(2-amino-acetyl)-piperazin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(7-[4-(Azetidine-3-carbonyl)-3-methyl-piperazin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(7-[4-(azetidine-3-carbonyl)-piperazin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(7-(3-amino-pyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid) 3-morpholino rifamycin S,25-O-desacetyl-(carbonyl-N-(8-chloro-1-cyclopropyl-6-fluoro-7-(3-formylamino-pyrrolidin-1-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid)-3-morpholino-11-deoxy-11-hydroxyiminorifamycin S, or25-O-desacetyl-(carbonyl-N-(2-dimethylamino-ethyl)-3-morpholino-11-deoxy-11-hydroxyiminorifamycinS.
 11. The compound of claim 10, wherein the structural formula is:


12. The compound of claim 10, wherein the structural formula is:


13. The compound of claim 10, wherein the structural formula is:


14. A method of treating a microbial infection in a subject comprising:administering to the subject an effective amount of a compound having aformula:

or its corresponding quinone form:

or its salts, hydrates, prodrugs or mixtures thereof; wherein, X ishydrogen, —NR₁₁R₁₂, —CH₂NR₁₁R₁₂, —C═NNR₁₁R₁₂, —SR₁₃, or -L₃-Q₃, whereinL₃ is any combination of 1 to 5 of the following structures:(C₁-C₆)alkylene, (C₁-C₆)alkenylene, (C₁-C₆)alkynylene,(C₃-C₈)cycloalkylene, heterocycle having from 1 to 3 heteroatoms,arylene, and heteroarylene, wherein L₃ optionally has any combination of1 to 3 heteroatoms selected from N, O and S, and wherein the carbon ornitrogen atoms of L₃ are optionally substituted by any combination of 1to 3 substituents selected from (C₁-C₆)alkyl, heterocycloalkyl, amino,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, hydroxyl, and (C₁-C₆)alkoxy,wherein R₁₁ and R₁₂ independently are hydrogen, (C₁-C₆)alkyl, orsubstituted (C₁-C₆)alkyl, or R₁₁ and R₁₂, together with the nitrogenatom to which they are attached, form a 4- to 8-membered heterocyclicring, optionally containing a second heteroatom selected from oxygen,nitrogen and sulfur, wherein one of the carbon or nitrogen atoms of theheterocyclic ring is optionally substituted by (C₁-C₆)alkyl orsubstituted (C₁-C₆)alkyl, and wherein R₁₃ is (C₁-C₆)alkyl or substituted(C₁-C₆)alkyl; Y is OR₁, when the compound is the Formula I, wherein R₁is hydrogen, (C₁-C₆)alkyl, substituted (C₁-C₆)alkyl, —CH₂COOH, or—CH₂CONR₁₁R₁₂, or Y is ═O, when the compound is the Formula II, or X andY, together with C-3 and C-4 of the Formula I or Formula II, jointogether to form a heterocyclic ring as shown in any of Formulas III,IV, V or VI:

wherein R₁₅ is —NR₂₀R₂₁, R₁₆ is hydrogen, OH or NH₂, R₁₇ is hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, (C₃-C₈)cycloalkyl, aryl,heteroaryl, or heterocycloalkyl, R₁₈ is (C₁-C₆)alkyl, (C₁-C₆)alkenyl,(C₁-C₆)alkynyl, (C₃-C₈)cycloalkyl, aryl, heteroaryl, —NR₂₀R₂₁, orheterocycloalkyl, R₁₉ is (C₁-C₆)alkyl or —NR₂₀R₂₁, R₂₀ and R₂₁independently are alkyl, cycloalkyl, aryl, or heteroaryl, or R₂₀ andR₂₁, together with the nitrogen atom to which they are attached, form a4-8 membered heterocyclic ring containing one or two heteroatomsoptionally substituted with hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkenyl,(C₁-C₆)alkynyl, or (C₃-C₈)cycloalkyl; Z is ═O, ═NH or ═NOR₁₄, whereinR₁₄ is —H, alkyl, aryl, heteroaryl or -L₁₁-Q₁₁, wherein L₁₁ is anycombination of 1 to 5 of the following structures: (C₁-C₆)alkylene,(C₁-C₆)alkenylene, (C₁-C₆)alkynylene, (C₃-C₈)cycloalkylene, heterocyclecontaining 1 to 3 heteroatoms, arylene, and heteroarylene, wherein L₁₁optionally has any combination of 1 to 3 heteroatoms selected from N, Oand S, and wherein the carbon or nitrogen atoms of L₁₁ are optionallysubstituted by any combination of 1 to 3 substituents selected from(C₁-C₆)alkyl, heterocycloalkyl, amino, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, hydroxyl, and (C₁-C₆)alkoxy; R₂ and R₃independently are hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkenyl,(C₁-C₆)alkynyl, aryl, heteroaryl or -L₂₅-Q₂₅, wherein L₂₅ is anycombination of 1 to 5 of the following structures: (C₁-C₆)alkylene,(C₁-C₆)alkenylene, (C₁-C₆)alkynylene, (C₃-C₈)cycloalkylene, heterocyclecontaining 1 to 3 heteroatoms, arylene, and heteroarylene, wherein L₂₅optionally has any combination of 1 to 3 heteroatoms selected from N, Oand S, and wherein the carbon or nitrogen atoms of L₂₅ are optionallysubstituted by any combination of 1 to 3 substituents selected from(C₁-C₆)alkyl, heterocycloalkyl, amino, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, hydroxyl, and (C₁-C₆)alkoxy, or R₂ and R₃, togetherwith the nitrogen atom to which they are attached, form a 4- to8-membered heterocyclic ring containing one or two heteroatoms, whereinthe carbon or nitrogen atoms of the ring are optionally substituted withone or more of hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, hydroxyl, and (C₁-C₆)alkoxy; and Q₃, Q₁₁, and Q₂₅are a pharmacophore, therapeutic drug, or antibacterial agentindependently comprising a quinolone, a macrolide, an oxazolidinone, anaminoglycoside, a tetracycline or any antibacterial pharmacophore. 15.The method of claim 14, wherein the composition is administered to thesubject in a total daily dose that is in the range of about 0.1 to about100 mg/kg body weight of the subject.
 16. The method of claim 14,wherein the microbial infection is caused by a drug-resistant bacterium.17. An antibiotic composition comprising: (a) a pharmaceuticalacceptable carrier; and (b) a therapeutically effective amount of acompound having a formula:

or its corresponding quinone form:

or its salts, hydrates, prodrugs or mixtures thereof; wherein, X ishydrogen, —NR₁₁R₁₂, —CH₂NR₁₁R₁₂, —C═NNR₁₁R₁₂, —SR₁₃, or -L₃-Q₃, whereinL₃ is any combination of 1 to 5 of the following structures:(C₁-C₆)alkylene, (C₁-C₆)alkenylene, (C₁-C₆)alkynylene,(C₃-C₈)cycloalkylene, heterocycle having from 1 to 3 heteroatoms,arylene, and heteroarylene, wherein L₃ optionally has any combination of1 to 3 heteroatoms selected from N, O and S, and wherein the carbon ornitrogen atoms of L₃ are optionally substituted by any combination of 1to 3 substituents selected from (C₁-C₆)alkyl, heterocycloalkyl, amino,(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, hydroxyl, and (C₁-C₆)alkoxy,wherein R₁₁ and R₁₂ independently are hydrogen, (C₁-C₆)alkyl, orsubstituted (C₁-C₆)alkyl, or R₁₁ and R₁₂, together with the nitrogenatom to which they are attached, form a 4- to 8-membered heterocyclicring, optionally containing a second heteroatom selected from oxygen,nitrogen and sulfur, wherein one of the carbon or nitrogen atoms of theheterocyclic ring is optionally substituted by (C₁-C₆)alkyl orsubstituted (C₁-C₆)alkyl, and wherein R₁₃ is (C₁-C₆)alkyl or substituted(C₁-C₆)alkyl; Y is OR₁, when the compound is the Formula I, wherein R₁is hydrogen, (C₁-C₆)alkyl, substituted (C₁-C₆)alkyl, —CH₂COOH, or—CH₂CONR₁₁R₁₂, or Y is ═O, when the compound is the Formula II, or X andY, together with C-3 and C-4 of the Formula I or Formula II, jointogether to form a heterocyclic ring as shown in any of Formulas III,IV, V or VI:

wherein R₁₅ is —NR₂₀R₂₁, R₁₆ is hydrogen, OH or NH₂, R₁₇ is hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, (C₃-C₈)cycloalkyl, aryl,heteroaryl, or heterocycloalkyl, R₁₈ is (C₁-C₆)alkyl, (C₁-C₆)alkenyl,(C₁-C₆)alkynyl, (C₃-C₈)cycloalkyl, aryl, heteroaryl, —NR₂₀R₂₁, orheterocycloalkyl, R₁₉ is (C₁-C₆)alkyl or —NR₂₀R₂₁, R₂₀ and R₂₁independently are alkyl, cycloalkyl, aryl, or heteroaryl, or R₂₀ andR₂₁, together with the nitrogen atom to which they are attached, form a4-8 membered heterocyclic ring containing one or two heteroatomsoptionally substituted with hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkenyl,(C₁-C₆)alkynyl, or (C₃-C₈)cycloalkyl; Z is ═O, ═NH or ═NOR₁₄, whereinR₁₄ is —H, alkyl, aryl, heteroaryl or -L₁₁-Q₁₁, wherein L₁₁ is anycombination of 1 to 5 of the following structures: (C₁-C₆)alkylene,(C₁-C₆)alkenylene, (C₁-C₆)alkynylene, (C₃-C₈)cycloalkylene, heterocyclecontaining 1 to 3 heteroatoms, arylene, and heteroarylene, wherein L₁₁,optionally has any combination of 1 to 3 heteroatoms selected from N, Oand S, and wherein the carbon or nitrogen atoms of L₁₁ are optionallysubstituted by any combination of 1 to 3 substituents selected from(C₁-C₆)alkyl, heterocycloalkyl, amino, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, hydroxyl, and (C₁-C₆)alkoxy; R₂ and R₃independently are hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkenyl,(C₁-C₆)alkynyl, aryl, heteroaryl or -L₂₅-Q₂₅, wherein L₂₅ is anycombination of 1 to 5 of the following structures: (C₁-C₆)alkylene,(C₁-C₆)alkenylene, (C₁-C₆)alkynylene, (C₃-C₈)cycloalkylene, heterocyclecontaining 1 to 3 heteroatoms, arylene, and heteroarylene, wherein L₂₅optionally has any combination of 1 to 3 heteroatoms selected from N, Oand S, and wherein the carbon or nitrogen atoms of L₂₅ are optionallysubstituted by any combination of 1 to 3 substituents selected from(C₁-C₆)alkyl, heterocycloalkyl, amino, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, hydroxyl, and (C₁-C₆)alkoxy, or R₂ and R₃, togetherwith the nitrogen atom to which they are attached, form a 4- to8-membered heterocyclic ring containing one or two heteroatoms, whereinthe carbon or nitrogen atoms of the ring are optionally substituted withone or more of hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylamino,di(C₁-C₆)alkylamino, hydroxyl, and (C₁-C₆)alkoxy; and Q₃, Q₁₁, and Q₂₅are a pharmacophore, therapeutic drug, or antibacterial agentindependently comprising a quinolone, a macrolide, an oxazolidinone, anaminoglycoside, a tetracycline or any antibacterial pharmacophore. 18.The antibiotic composition of claim 17, wherein the pharmaceuticalacceptable carrier is an injectable solution, suspension, or emulsion.19. The antibiotic composition of claim 17, wherein the pharmaceuticalacceptable carrier is a non-irritating excipient.
 20. The antibioticcomposition of claim 17, wherein the pharmaceutical acceptable carrieris a liquid emulsion, microemulsion, solution, suspension, syrum orelixir sutable for oral administration to a subject.
 21. The antibioticcomposition of claim 17, wherein the pharmaceutically acceptable carrieris a filler, binder, humectant, disintegrating agent, solution retardingagent, absorption accelerator, wetting agent, or lubricant that issutable for oral administration to a subject.